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 [Diuretic] TL Ceiling Effect Log [Diuretic] TL Fractional Excretion of Sodium (%)

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

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

7. 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

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

10. 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

11. 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)

12. 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

13. 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)

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

15. 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

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 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