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