DIURETICS
How do they work?What do they do?
When do I use them?HOW DO I USE THEM?
0.01 0.1 1 10 100 1000 100000
50
100
150
Dose
Response
CONCEPT OF CEILING DOSE
Ceiling [Diuretic]TL
Ceiling Effect
Log [Diuretic]TL
Fra
ctio
nal
Exc
reti
on o
f S
odiu
m (
%)
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-MaximalDiuretic Response.
CONCEPT OF CEILING DOSE
EFFECT
< Ceiling 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, toexceed ceiling dose of diuretic!!
No AdditionalEffect
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 UrinaryProteins (e.g., Nephrotic Syndrome) Increase
CEILING DOSES FOR I.V. LOOP DIURETICS(in mgs)
CIRRHOSIS HEART FAILURE
40 to 80
1 to 2
10 to 20
NEPHROTICSYNDROME
AFR/CRFModerate
AFR/CRFSevere
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 BindingIncreases Ceiling
Dose
Impaired DeliveryIncreases Ceiling
Dose
CONVERTING I.V. DOSING TOORAL DOSING
BIOAVAILABILITY CONVERSION FACTOR
~ 50% (highly variable)
~ 100%
~ 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
DiseaseDiminished 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)
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)
MECHANISMS OF DIURETIC RESISTANCE
Proximal Distal
Na Na
Proximal Distal
Na
Proximal Distal
Na Na
Na
Proximal Distal
Na Na
AcuteLoop
ChronicLoop
ChronicLoop + Thiazide
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)
RATIONALE FOR MORE FREQUENT DOSINGOR CONTINUOUS I.V. INFUSION
[Diuretic]TL Ceiling
[Diuretic]TL
[Diuretic]TL
Ceiling
Ceiling
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
WHAT HAPPENS WHEN [DIURETIC]IN TUBULAR LUMEN IS LESS
THAN CEILING??
Postdiuresis Sodium Retention!!
RATIONALE FOR LOW SODIUM DIET
A low sodium diet attenuates postdiureticsodium retention, thereby lowering diuretic
requirements!!
Major Problem is Compliance
IMPORTANT DRUG INTERACTIONS
NSAIDSSalt
DecongestantsProbenecid
Hyperkalemia-Induced by K-Sparing
Diuretics
Enhanced Ototoxicityof Loop Diuretic
DiminishedDiureticResponse
ACE InhibitorsBeta-Blockers
K SupplementsK-Sparing Diuretics
Heparin
Ototoxic Drugs
ARF/CRF Nephrotic Syndrome Cirrhosis Mild CHFSevere/Moderate
CHF
DROP Thiazide &ADD Loop Diuretic:1) Titrate Single Daily Dose to Ceiling2) 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 Algorithmfor K Homeostasis.)
While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion
SpironolactoneTitrated to 400 mgDaily.
ADD Thiazide:•If CrCl > 50•50 to 100 mg/d HCTZ