Pharmacology of Diuretics

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DIURETICS : 

DIURETICS University of Pittsburgh School of Medicine Center for Clinical Pharmacology Edwin K. Jackson, Ph.D.

DIURETICS: 

DIURETICS HOW DO THEY WORK? What do they do? When do I use them? How do I use them?

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RENAL ANATOMY & PHYSIOLOGY

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Renal Circulation

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Nephron

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Glomerulus Macula Densa

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Glomerular Capillaries

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Nephron

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Epithelial Cell

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EPITHELIAL TRANSPORT

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MECHANISM OF ACTION

Na-K-2Cl SYMPORT INHIBITORS: 

Na-K-2Cl SYMPORT INHIBITORS Also Called: Loop Diuretics High Ceiling Diuretics Ethacrynic Acid (EDECRIN) Torsemide (DEMADEX) Bumetanide (BUMEX) Furosemide (LASIX)

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(Bartter’s Syndrome)

Na-Cl SYMPORT INHIBITORS: 

Na-Cl SYMPORT INHIBITORS Also Called: Thiazide Diuretics Thiazide-Like Diuretics Chlorthalidone (HYGROTON) Metolazone (ZAROXOLYN) Chlorothiazide (DIURIL) Hydrochlorothiazide (HYDRODIURIL)

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(Gitelman’s Syndrome)

Na CHANNEL INHIBITORS: 

Na CHANNEL INHIBITORS Also Called: K-Sparing Diuretics Amiloride (MIDAMOR) Triamterene (DYRENIUM)

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(Liddle’s Syndrome)

MINERALOCORTICOID RECEPTOR ANTAGONISTS : 

MINERALOCORTICOID RECEPTOR ANTAGONISTS Also Called: K-Sparing Diuretics Aldosterone Antagonists Spironolactone (ALDACTONE) Eplerenone (INSPRA)

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(Syndrome of Apparent MC excess) (Licorice: Glycyrrhizic Acid)

DIURETICS: 

DIURETICS How do they work? WHAT DO THEY DO? When do I use them? How do I use them?

Na-K-2Cl SYMPORT INHIBITORS: 

Na-K-2Cl SYMPORT INHIBITORS Also Called: Loop Diuretics High Ceiling Diuretics Ethacrynic Acid Torsemide Bumetanide Furosemide

THERAPEUTIC EFFECTS: 

THERAPEUTIC EFFECTS Increase Na Excretion to 25% of Filtered Load Treatment for Oliguric ARF Increase Ca Excretion Treatment for Hypercalcemia Impair Free Water Reabsorption Treatment for Hyponatremia Increase Venous Capacitance Treatment for Pulmonary Edema Increase Urine Volume Treatment for Severe Edema

ADVERSE EFFECTS: 

ADVERSE EFFECTS Hypomagnesemia Metabolic Alkalosis Hypokalemia Profound ECFV Depletion Hyperglycemia Hyperuricemia Ototoxicity Hypocalcemia

OTHER EFFECTS: 

OTHER EFFECTS Increase & Redistribute RBF Increase Renin Release Release PGs Block TGF

Na-Cl SYMPORT INHIBITORS: 

Na-Cl SYMPORT INHIBITORS Also Called: Thiazide Diuretics Thiazide-Like Diuretics Chlorthalidone Metolazone Chlorothiazide Hydrochlorothiazide

THERAPEUTIC EFFECTS: 

THERAPEUTIC EFFECTS Increase Na Excretion to 5% of Filtered Load Treatment for Hypertension Decrease Ca Excretion Treatment for Calcium Nephrolithiasis Treatment for Nephrogenic Diabetes Insipidus Treatment for Mild Edema

ADVERSE EFFECTS: 

ADVERSE EFFECTS Hypomagnesemia Metabolic Alkalosis Hypokalemia ECFV Depletion Hyperglycemia Hyperuricemia Hyponatremia Hypercalcemia Impotence Increased LDL (Renal Cell Carcinoma??)

OTHER EFFECTS: 

OTHER EFFECTS Nothing of Clinical Significance

Na CHANNEL INHIBITORS: 

Na CHANNEL INHIBITORS Also Called: K-Sparing Diuretics Amiloride Triamterene

THERAPEUTIC EFFECTS: 

THERAPEUTIC EFFECTS Enhance Natriuresis Caused by Other Diuretics Block Na Channels Treatment for Liddle’s Syndrome Prevent Hypokalemia Used in Combination with Loop & Thiazide Diuretics Treatment for Lithium-Induced Diabetes Insipidus

ADVERSE EFFECTS: 

ADVERSE EFFECTS Renal Stones Interstitial Nephritis Megaloblastosis Hyperkalemia Hyperkalemia Amiloride Triamterene

OTHER EFFECTS: 

OTHER EFFECTS Nothing of Clinical Significance

MINERALOCORTICOID RECEPTOR ANTAGONISTS : 

MINERALOCORTICOID RECEPTOR ANTAGONISTS Also Called: K-Sparing Diuretics Aldosterone Antagonists Spironolactone Eplerenone

THERAPEUTIC EFFECTS: 

THERAPEUTIC EFFECTS Enhances Natriuresis Caused by Other Diuretics Blocks Aldosterone Treatment for Primary Hyper-aldosteronism Prevents Hypokalemia Used in Combination with Loop & Thiazide Diuretics Treatment for Edema of Liver Cirrhosis Treatment for Hypertension Treatment for Heart Failure

ADVERSE EFFECTS: 

ADVERSE EFFECTS Impotence Gynecomastia Metabolic Acidosis Hyperkalemia Hirsutism CNS Side Effects Peptic Ulcers Gastritis Menstrual Irregularities Deepening of Voice

OTHER EFFECTS: 

OTHER EFFECTS Nothing of Clinical Significance

DIURETICS: 

DIURETICS How do they work? What do they do? WHEN DO I USE THEM? How do I use them?

DEFINITION OF EDEMA : 

DEFINITION OF EDEMA The Accumulation of Abnormal Amounts of Extravascular, Extracellular Fluid. ANASARCA: Severe, widely distributed pitting edema.

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TYPES OF EDEMA LOCALIZED GENERALIZED Inflammation Lymphatic Obstruction Venous Obstruction Thrombophlebitis CARDIAC HEPATIC RENAL NEPHROTIC SYNDROME ACUTE GN CRF IDIOPATHIC OTHER Cyclic Myxedema Vasodilator-induced Pregnancy-induced Capillary leak syndrome

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MECHANISMS OF EDEMA FORMATION  IS P cap  cap P IS  alance of Starling Forces Filtration < or = Lymphatic Drainage Filtration > Lymphatic Drainage  o  dema  DEMA (Capillary Permeability)  nterstitial Space

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CARDIAC EDEMA Diagnosis History of Heart Disease Evidence of Pulmonary Edema Orthopnea SOB Exertional Dyspnea Evidence of Volume Expansion Hepatic Congestion Hepatojugular Reflux Ventricular Gallop Rhythm

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CARDIAC EDEMA Pathophysiology HEART DISEASE Left Ventricular Dysfunction Right Ventricular Dysfunction Increased Pulmonary Venous Pressure Pulmonary Edema Systemic Edema Hypotension Renal Na Retention

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HEPATIC EDEMA Diagnosis History of Liver Disease Diminished CrCl (Normal Serum Cr) Evidence of Chronic Liver Disease Spider Angiomata Palmar Erythema Jaundice Hypoalbuminemia Evidence of Portal Hypertension Venous Pattern on Abdominal Wall Esophogeal Varices Ascites

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LIVER DISEASE Neurohumoral Activation (Increased “Volume Hormones”) Liver Cirrhosis Increased Pressure in Hepatic Sinusoids Exudation of Fluid Into Peritoneal Cavity Systemic Edema Ascites Renal Na Retention HEPATIC EDEMA Pathophysiology Functional Renal Insufficiency (Hepatorenal Syndrome)

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RENAL EDEMA Diagnosis History of Renal Disease Evidence of Albumin Loss Narrow, pale transverse bands in nail beds Proteinuria (3+ to 4+) Hypoalbuminemia Renal Imaging Enlarged Kidneys Nephrotic Syndrome or AGN Shrunken Kidneys CRF

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RENAL EDEMA Diagnosis Nephrotic Syndrome Hyaline Casts Oval Fat Bodies Lipid Droplets/Casts Acute Glomerulonephritis Hematuria Erythrocyte Casts Leukocyte Casts Pyuria Chronic Renal Failure Broad Waxy Casts Urinalysis

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RENAL EDEMA Pathophysiology RENAL DISEASE Urinary Loss of Albumin Reduced GFR Hypoalbuminemia Altered Starling Forces Systemic Edema Renal Na Retention NEPHROTIC PATHWAY NEPHRITIC PATHWAY

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CARDIAC Dependent Edema HEPATIC RENAL Proteinuria Facial Edema Ascites Hypoalbuminemia Severe Absent Absent Absent/Mild Severe Absent/Mild Severe Moderate/Mild Absent Absent/Trace Absent/Trace Severe/Moderate Moderate Mild Severe

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IDIOPATHIC EDEMA Diagnosis Women of Childbearing Age Associated with Eating Disorders Dependent Edema Facial Edema Abdominal Bloating 

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IDIOPATHIC EDEMA Pathophysiology  IS P cap  cap P IS  alance of Starling Forces Filtration > Lymphatic Drainage  DEMA (Capillary Permeability)  nterstitial Space   

DIURETICS: 

DIURETICS How do they work? What do they do? When do I use them? HOW DO I USE THEM?

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CONCEPT OF CEILING DOSE Ceiling [Diuretic] TL Ceiling Effect Log [Diuretic] TL Fractional Excretion of Sodium (%)

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CONCEPT OF CEILING DOSE Dose of Diuretic that Achieves a Ceiling [Diuretic] in the Tubular Lumen. Said Differently Dose of Diuretic that Yields a Near-Maximal Diuretic Response.

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CONCEPT OF CEILING DOSE EFFECT < Ceiling Effect Ceiling Effect Ceiling Effect ACTUAL DOSE < Ceiling Dose Ceiling Dose > Ceiling Dose

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CONCEPT OF CEILING DOSE Exceeding Ceiling Dose Yields: Pointless, and possibly harmful, to exceed ceiling dose of diuretic!! No Additional Effect Possible Adverse Effects

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DETERMINANTS OF CEILING DOSE VARIABLE Ceiling Dose Depends on: Diuretic Disease Increased Potency Decrease CEILING DOSE Decreased Tubular Transport (e.g., ARF/CRF) Increase Increased Binding to Urinary Proteins (e.g., Nephrotic Syndrome) Increase

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CEILING DOSES FOR I.V. LOOP DIURETICS (in mgs) CIRRHOSIS HEART FAILURE 40 to 80 1 to 2 10 to 20 NEPHROTIC SYNDROME AFR/CRF Moderate AFR/CRF Severe 160 to 200 8 to 10 50 to 100 80 to 160 4 to 8 20 to 50 80 to 120 2 to 3 20 to 50 40 to 80 1 to 2 10 to 20 Furosemide Bumetanide Torsemide Protein Binding Increases Ceiling Dose Impaired Delivery Increases Ceiling Dose

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CONVERTING I.V. DOSING TO ORAL DOSING BIOAVAILABILITY CONVERSION FACTOR ~ 50% (highly variable) ~ 100% ~ 100% 2 or higher 1 1 Furosemide Bumetanide Torsemide

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DETERMINANTS OF CEILING EFFECT VARIABLE Ceiling Effect Depends on: Diuretic Disease Diuretic Loop > Thiazide > K-Sparing CEILING EFFECT Disease Diminished Nephron Response in Nephrotic Syndrome, Cirrhosis, & Heart Failure.

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MECHANISMS OF DIURETIC RESISTANCE MECHANISM Patient Counseling SOLUTION Patient Counseling Push to Ceiling Dose Noncompliance NSAIDS Decreased Tubular Transport (e.g., ARF & CRF) Bed Rest Decreased RBF

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MECHANISMS OF DIURETIC RESISTANCE (Continued) MECHANISM SOLUTION Bed Rest More Frequent Dosing or Continuous Infusion Combination Therapy (Sequential Blockade) Changes in “Volume Hormones” (SNS, RAS, ADH & ANF) Compensation by Distal Nephron Diminished Nephron Response (CHF, Cirrhosis, Nephrotic Syndrome)

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MECHANISMS OF DIURETIC RESISTANCE Proximal Distal Na Na Proximal Distal Na Proximal Distal Na Na Na Proximal Distal Na Na Acute Loop Chronic Loop Chronic Loop + Thiazide

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MECHANISMS OF DIURETIC RESISTANCE (Continued) MECHANISM SOLUTION Bed Rest More Frequent Dosing or Continuous Infusion Combination Therapy (Sequential Blockade) Changes in “Volume Hormones” (SNS, RAS, ADH & ANF) Compensation by Distal Nephron Diminished Nephron Response (CHF, Cirrhosis, Nephrotic Syndrome)

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RATIONALE FOR MORE FREQUENT DOSING OR CONTINUOUS I.V. INFUSION [Diuretic] TL Ceiling [Diuretic] TL [Diuretic] TL Ceiling Ceiling

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CEILING DOSES FOR CONTINUOUS I.V. INFUSION OF LOOP DIURETICS (in mgs per hour) LOADING DOSE (in mgs) CrCl < 25 10 0.5 5 10 to 20 0.5 to 1 5 to 10 20 to 40 1 to 2 10 to 20 40 1 20 Furosemide Bumetanide Torsemide CrCl: 25 to 75 CrCl > 75

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WHAT HAPPENS WHEN [DIURETIC] IN TUBULAR LUMEN IS LESS THAN CEILING?? Postdiuresis Sodium Retention!!

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RATIONALE FOR LOW SODIUM DIET A low sodium diet attenuates postdiuretic sodium retention, thereby lowering diuretic requirements!! Major Problem is Compliance

IMPORTANT DRUG INTERACTIONS: 

IMPORTANT DRUG INTERACTIONS NSAIDS Salt Decongestants Probenecid Hyperkalemia- Induced by K-Sparing Diuretics Enhanced Ototoxicity of Loop Diuretic Diminished Diuretic Response ACE Inhibitors Beta-Blockers K Supplements K-Sparing Diuretics Heparin Ototoxic Drugs

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Chronic Renal Failure Nephrotic Syndrome Cirrhosis Mild CHF Moderate or Severe CHF Loop Diuretic: Titrate Single Daily Dose up to Ceiling Dose as Needed Thiazide Diuretic: CrCl > 50, use 25 to 50 mg/d HCTZ CrCl 20 to 50, use 50 to 100 mg/d HCTZ CrCl < 20, use 100 to 200 mg/d HCTZ K + -Sparing Diuretic: If CrCl > 75 & urinary [Na]:[K] ratio is < 1 (Note: May add K-Sparing Diuretic to Loop and/or Thiazide Diuretic at Any Point in Algorithm for K + Homeostasis.) Add While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion Spironolactone: Titrate up to 400 mg/d as needed. CrCl< 50 Thiazide: 50 to 100 mg/d HCTZ CrCl> 50 CrCl< 50 CrCl>50 Drop Thiazide Add Loop Diuretic: Increase Frequency of Ceiling Dose as Needed: Furosemide, up to 3X daily; Bumetanide, up to 4X daily; Torsemide, up to 2X daily Add Add

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Reading Assignment Chapter 54 – Diuretics By Christopher S. Wilcox In Brenner and Rector’s The Kidney 7 th Edition, 2004 Available online via HSL Online Resources (Electronic Books)