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
150
Response
Sodium (%)
Ceiling Effect
100
50
Ceiling [Diuretic]TL
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 Dose Ceiling Effect
CONCEPT OF CEILING DOSE
Pointless, and possibly harmful, to
exceed ceiling dose of diuretic!!
Exceeding Ceiling Dose Yields:
No Additional Possible Adverse
Effect Effects
DETERMINANTS OF CEILING DOSE
Ceiling Dose Depends on:
•Diuretic
•Disease
VARIABLE CEILING DOSE
Increased Potency Decrease
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)
NEPHROTIC AFR/CRF AFR/CRF
CIRRHOSIS HEART FAILURE SYNDROME Moderate Severe
Furosemide 40 to 80 40 to 80 80 to 120 80 to 160 160 to 200
Bumetanide 1 to 2 1 to 2 2 to 3 4 to 8 8 to 10
Torsemide 10 to 20 10 to 20 20 to 50 20 to 50 50 to 100
Protein Binding Impaired Delivery
Increases Ceiling Increases Ceiling
Dose Dose
CONVERTING I.V. DOSING TO
ORAL DOSING
BIOAVAILABILITY CONVERSION FACTOR
Furosemide ~ 50% (highly variable) 2 or higher
Bumetanide ~ 100% 1
Torsemide ~ 100% 1
DETERMINANTS OF CEILING EFFECT
Ceiling Effect Depends on:
•Diuretic
•Disease
VARIABLE CEILING EFFECT
Diuretic Loop > Thiazide > K-Sparing
Diminished Nephron Response
Disease in Nephrotic Syndrome, Cirrhosis,
& Heart Failure.
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
MECHANISMS OF DIURETIC RESISTANCE
(Continued)
MECHANISM SOLUTION
Changes in “Volume Hormones”
(SNS, RAS, ADH & ANF) Bed Rest
Compensation by Distal Nephron Combination Therapy
(Sequential Blockade)
Diminished Nephron Response
(CHF, Cirrhosis, Nephrotic Syndrome) More Frequent Dosing or Continuous Infusion
MECHANISMS OF DIURETIC RESISTANCE
Proximal Distal
Na Na
Proximal Distal
Acute
Loop Na Na
Proximal Distal
Chronic
Loop
Na Na
Chronic Proximal Distal
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 Combination Therapy
(Sequential Blockade)
Diminished Nephron Response
(CHF, Cirrhosis, Nephrotic Syndrome) 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 CrCl 75
(in mgs)
Furosemide 40 20 to 40 10 to 20 10
Bumetanide 1 1 to 2 0.5 to 1 0.5
Torsemide 20 10 to 20 5 to 10 5
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 Diminished
Decongestants Diuretic
Probenecid Response
ACE Inhibitors
Beta-Blockers Hyperkalemia-
K Supplements Induced by K-Sparing
K-Sparing Diuretics Diuretics
Heparin
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 ADD Thiazide:
2) Optimize Frequency of Ceiling Dose •If CrCl > 50
•Furosemide: up to 4X daily •50 to 100 mg/d HCTZ
•Bumetanide: up to 6X daily
•Torsemide: up to 3X daily
ADD K-Sparing Diuretic:
•If CrCl > 75 ADD Thiazide Diuretic:
•If Urinary [Na]:[K] ratio is 50, use 25 to 50 mg/d HCTZ
(Note: May add K-Sparing Diuretic to Loop •CrCl 20 to 50, use 50 to 100 mg/d HCTZ
and/or Thiazide Diuretic at Any Point in Algorithm •CrCl < 20, use 100 to 200 mg/d HCTZ
for K Homeostasis.)
While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion