Transcript Diuretics - Part 4: How Do I Use Them

DIURETICS
How do they work?
What do they do?
When do I use them?
HOW DO I USE THEM?
Fractional Excretion of
Response
Sodium (%)
CONCEPT OF CEILING DOSE
150
100
Ceiling Effect
50
Ceiling [Diuretic]TL
0
0.01
0.1
1
10 100 1000 10000
Log [Diuretic]
TL
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
Ceiling Dose
Ceiling 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
Effect
Possible Adverse
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)
CIRRHOSIS
HEART FAILURE
NEPHROTIC
SYNDROME
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
10 to 20
10 to 20
20 to 50
20 to 50
50 to 100
Torsemide
Protein Binding
Increases Ceiling
Dose
AFR/CRF
Moderate
AFR/CRF
Severe
Impaired Delivery
Increases Ceiling
Dose
CONVERTING I.V. DOSING TO
ORAL DOSING
BIOAVAILABILITY
Furosemide
~ 50% (highly variable)
CONVERSION FACTOR
2 or higher
Bumetanide
~ 100%
1
Torsemide
~ 100%
1
DETERMINANTS OF CEILING EFFECT
Ceiling Effect Depends on:
•Diuretic
•Disease
VARIABLE
Diuretic
Disease
CEILING EFFECT
Loop > Thiazide > K-Sparing
Diminished Nephron Response
in Nephrotic Syndrome, Cirrhosis,
& Heart Failure.
MECHANISMS OF DIURETIC RESISTANCE
MECHANISM
Noncompliance
NSAIDS
SOLUTION
Patient Counseling
Patient Counseling
Decreased Tubular Transport
(e.g., ARF & CRF)
Push to Ceiling Dose
Decreased RBF
Bed Rest
MECHANISMS OF DIURETIC RESISTANCE
(Continued)
MECHANISM
Changes in “Volume Hormones”
(SNS, RAS, ADH & ANF)
Compensation by Distal Nephron
Diminished Nephron Response
(CHF, Cirrhosis, Nephrotic Syndrome)
SOLUTION
Bed Rest
Combination Therapy
(Sequential Blockade)
More Frequent Dosing or Continuous Infusion
MECHANISMS OF DIURETIC RESISTANCE
Proximal
Distal
Na
Acute
Loop
Chronic
Loop
Chronic
Loop +
Thiazide
Proximal
Na
Distal
Na
Proximal
Na
Distal
Na
Proximal
Na
Na
Distal
Na
MECHANISMS OF DIURETIC RESISTANCE
(Continued)
MECHANISM
Changes in “Volume Hormones”
(SNS, RAS, ADH & ANF)
Compensation by Distal Nephron
Diminished Nephron Response
(CHF, Cirrhosis, Nephrotic Syndrome)
SOLUTION
Bed Rest
Combination Therapy
(Sequential Blockade)
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
(in mgs)
CrCl < 25
CrCl: 25 to 75
CrCl > 75
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
Decongestants
Probenecid
ACE Inhibitors
Beta-Blockers
K Supplements
K-Sparing Diuretics
Heparin
Ototoxic Drugs
Diminished
Diuretic
Response
HyperkalemiaInduced by K-Sparing
Diuretics
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
2) Optimize Frequency of Ceiling Dose
•Furosemide: up to 4X daily
•Bumetanide: up to 6X daily
•Torsemide: up to 3X daily
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:
•If CrCl > 50
•50 to 100 mg/d HCTZ
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