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

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

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 EFFECT < Ceiling Effect Ceiling Effect ACTUAL DOSE < Ceiling Dose Ceiling Dose > Ceiling Dose

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

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

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

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

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.

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

MECHANISMS OF DIURETIC RESISTANCE (Continued) MECHANISMSOLUTION 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)

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

MECHANISMS OF DIURETIC RESISTANCE (Continued) MECHANISMSOLUTION 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)

RATIONALE FOR MORE FREQUENT DOSING OR CONTINUOUS I.V. INFUSION [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 < to to 1 5 to to 40 1 to 2 10 to Furosemide Bumetanide Torsemide CrCl: 25 to 75CrCl > 75

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 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

ARF/CRFNephrotic SyndromeCirrhosisMild CHF Severe/Moderate CHF 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 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 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.) While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion Spironolactone Titrated to 400 mg Daily. ADD Thiazide: If CrCl > to 100 mg/d HCTZ