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DIURETICS

DIURETICS. How do they work? What do they do? When do I use them? HOW DO I USE THEM?. CONCEPT OF CEILING DOSE. Ceiling Effect. Fractional Excretion of Sodium (%). Ceiling [Diuretic] TL. Log [Diuretic] TL. CONCEPT OF CEILING DOSE. Dose of Diuretic that Achieves a Ceiling

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DIURETICS

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

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

  3. 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.

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

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

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

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

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

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

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

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

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

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

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

  15. 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 40 20 to 40 10 to 20 10 Furosemide 1 Bumetanide 1 to 2 0.5 to 1 0.5 20 10 to 20 5 to 10 5 Torsemide

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

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

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

  19. Severe/Moderate CHF ARF/CRF Nephrotic Syndrome 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

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