DIURETICS

DIURETICS How do they work? What do they do? When do I use them? HOW DO I USE THEM? CONCEPT OF CEILING DOSE Fractional Excretion of Response Sodium (%) 150 100 50 Ceiling [Diuretic]TL Ceiling Effect 0 0.01 0.1 1 10 100 Log [Diuretic]TL 1000 10000 Dose 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. CONCEPT OF CEILING DOSE ACTUAL DOSE EFFECT < Ceiling Effect Ceiling Effect Ceiling Effect < Ceiling Dose Ceiling Dose > Ceiling Dose CONCEPT OF CEILING DOSE Pointless, and possibly harmful, to exceed ceiling dose of diuretic!! Exceeding Ceiling Dose Yields: No Additional Effect Possible Adverse Effects DETERMINANTS OF CEILING DOSE Ceiling Dose Depends on: •Diuretic •Disease VARIABLE Increased Potency Decreased Tubular Transport (e.g., ARF/CRF) Increased Binding to Urinary Proteins (e.g., Nephrotic Syndrome) CEILING DOSE Decrease Increase Increase CEILING DOSES FOR I.V. LOOP DIURETICS (in mgs) CIRRHOSIS HEART FAILURE NEPHROTIC SYNDROME AFR/CRF Moderate AFR/CRF Severe Furosemide 40 to 80 1 to 2 10 to 20 40 to 80 1 to 2 10 to 20 80 to 120 2 to 3 20 to 50 80 to 160 4 to 8 20 to 50 160 to 200 8 to 10 50 to 100 Bumetanide Torsemide Protein Binding Increases Ceiling Dose Impaired Delivery Increases Ceiling Dose CONVERTING I.V. DOSING TO ORAL DOSING BIOAVAILABILITY CONVERSION FACTOR Furosemide ~ 50% (highly variable) ~ 100% ~ 100% 2 or higher 1 1 Bumetanide Torsemide DETERMINANTS OF CEILING EFFECT Ceiling Effect Depends on: •Diuretic •Disease VARIABLE CEILING EFFECT Diuretic Loop > Thiazide > K-Sparing Diminished Nephron Response in Nephrotic Syndrome, Cirrhosis, & Heart Failure. Disease MECHANISMS OF DIURETIC RESISTANCE MECHANISM Noncompliance SOLUTION Patient Counseling NSAIDS Decreased Tubular Transport (e.g., ARF & CRF) Patient Counseling Push to Ceiling Dose Decreased RBF Bed Rest MECHANISMS OF DIURETIC RESISTANCE (Continued) MECHANISM SOLUTION Changes in “Volume Hormones” (SNS, RAS, ADH & ANF) Bed Rest Compensation by Distal Nephron Diminished Nephron Response (CHF, Cirrhosis, Nephrotic Syndrome) Combination Therapy (Sequential Blockade) More Frequent Dosing or Continuous Infusion MECHANISMS OF DIURETIC RESISTANCE Proximal Distal Na Na Acute Loop Proximal Distal Na Proximal Distal Na Na Chronic Loop Na Proximal Distal Chronic Loop + Thiazide Na Na MECHANISMS OF DIURETIC RESISTANCE (Continued) MECHANISM SOLUTION Changes in “Volume Hormones” (SNS, RAS, ADH & ANF) Bed Rest Compensation by Distal Nephron Diminished Nephron Response (CHF, Cirrhosis, Nephrotic Syndrome) Combination Therapy (Sequential Blockade) More Frequent Dosing or Continuous Infusion RATIONALE FOR MORE FREQUENT DOSING OR CONTINUOUS I.V. INFUSION [Diuretic]TL Ceiling [Diuretic]TL Ceiling [Diuretic]TL Ceiling CEILING DOSES FOR CONTINUOUS I.V. INFUSION OF LOOP DIURETICS (in mgs per hour) LOADING DOSE (in mgs) CrCl < 25 CrCl: 25 to 75 CrCl > 75 Furosemide Bumetanide 40 1 20 to 40 10 to 20 10 1 to 2 10 to 20 0.5 to 1 5 to 10 0.5 5 Torsemide 20 WHAT HAPPENS WHEN [DIURETIC] IN TUBULAR LUMEN IS LESS THAN CEILING?? Postdiuresis Sodium Retention!! RATIONALE FOR LOW SODIUM DIET A low sodium diet attenuates postdiuretic sodium retention, thereby lowering diuretic requirements!! Major Problem is Compliance IMPORTANT DRUG INTERACTIONS NSAIDS Salt Decongestants Probenecid ACE Inhibitors Beta-Blockers K Supplements K-Sparing Diuretics Heparin Diminished Diuretic Response HyperkalemiaInduced by K-Sparing Diuretics Ototoxic Drugs Enhanced Ototoxicity of Loop Diuretic Severe/Moderate ARF/CRF Nephrotic Syndrome CHF Cirrhosis Mild CHF Spironolactone Titrated to 400 mg Daily. DROP Thiazide &ADD Loop Diuretic: 1) Titrate Single Daily Dose to Ceiling 2) Optimize Frequency of Ceiling Dose •Furosemide: up to 4X daily •Bumetanide: up to 6X daily •Torsemide: up to 3X daily ADD Thiazide: •If CrCl > 50 •50 to 100 mg/d HCTZ ADD K-Sparing Diuretic: •If CrCl > 75 •If 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 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 While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion