DIURETICS DIURETICS

University of PittsburghSchool of Medicine

Center for Clinical Pharmacology

Edwin K. Jackson, Ph.D.

DIURETICS

HOW DO THEY WORK?What do they do?

When do I use them?How do I use them?

RENALANATOMY &PHYSIOLOGY

Renal Circulation

Nephron

Glomerulus

Macula Densa

Glomerular Capillaries

Nephron

Epithelial Cell

EPITHELIALTRANSPORT

MECHANISMOF ACTION

Na-K-2Cl SYMPORT INHIBITORS

Also Called:•Loop Diuretics•High Ceiling Diuretics

EthacrynicAcid

(EDECRIN)

Torsemide(DEMADEX)

Bumetanide(BUMEX)

Furosemide(LASIX)

(Bartter’s Syndrome)

Na-Cl SYMPORT INHIBITORS

Also Called:•Thiazide Diuretics•Thiazide-Like Diuretics

ChlorthalidoneChlorthalidone(HYGROTON)(HYGROTON)

Metolazone(ZAROXOLYN)

Chlorothiazide(DIURIL)

Hydrochlorothiazide(HYDRODIURIL)

(Gitelman’s Syndrome)

Na CHANNELINHIBITORS

Also Called:•K-Sparing Diuretics

Amiloride(MIDAMOR)

Triamterene(DYRENIUM)

(Liddle’s Syndrome)

MINERALOCORTICOID RECEPTOR ANTAGONISTS

Also Called:•K-Sparing Diuretics•Aldosterone Antagonists

Spironolactone(ALDACTONE)

Eplerenone(INSPRA)

(Syndrome of Apparent MC excess)(Licorice: Glycyrrhizic Acid)

DIURETICS

How do they work?WHAT DO THEY DO?

When do I use them?How do I use them?

Na-K-2Cl SYMPORT INHIBITORS

Also Called:•Loop Diuretics•High Ceiling Diuretics

EthacrynicAcid

TorsemideBumetanide

Furosemide

THERAPEUTIC EFFECTSIncrease Na Excretion

to 25% of Filtered Load

Treatment forOliguric ARF

Increase Ca Excretion Treatment for Hypercalcemia

Impair Free WaterReabsorption

Treatment forHyponatremia

Increase VenousCapacitance

Treatment forPulmonary

Edema

Increase Urine Volume

Treatment forSevere Edema

ADVERSE EFFECTS

Hypomagnesemia

MetabolicAlkalosis

Hypokalemia

Profound ECFVDepletion

Hyperglycemia

Hyperuricemia

Ototoxicity

Hypocalcemia

OTHER EFFECTS

Increase &Redistribute

RBF

Increase ReninRelease

Release PGs Block TGF

Na-Cl SYMPORT INHIBITORS

Also Called:•Thiazide Diuretics•Thiazide-Like Diuretics

Chlorthalidone

MetolazoneChlorothiazide

Hydrochlorothiazide

THERAPEUTIC EFFECTSIncrease Na Excretionto 5% of Filtered Load

Treatment forHypertension

Decrease Ca ExcretionTreatment for

Calcium Nephrolithiasis

Treatment forNephrogenic

Diabetes Insipidus

Treatment forMild Edema

ADVERSE EFFECTS

Hypomagnesemia

MetabolicAlkalosis

Hypokalemia

ECFVDepletion

Hyperglycemia

Hyperuricemia

Hyponatremia

Hypercalcemia

Impotence Increased LDL

(Renal Cell Carcinoma??)

OTHER EFFECTS

Nothing ofClinical

Significance

Na CHANNELINHIBITORS

Also Called:•K-Sparing Diuretics

AmilorideTriamterene

THERAPEUTIC EFFECTSEnhance Natriuresis

Caused by Other Diuretics

Block Na Channels

Treatment for Liddle’s

Syndrome

Prevent Hypokalemia

Used in Combination with Loop &

Thiazide Diuretics

Treatment for Lithium-Induced Diabetes Insipidus

ADVERSE EFFECTS

Renal Stones

InterstitialNephritis

Megaloblastosis

HyperkalemiaHyperkalemia

AmilorideTriamterene

OTHER EFFECTS

Nothing ofClinical

Significance

MINERALOCORTICOID RECEPTOR ANTAGONISTS

Also Called:•K-Sparing Diuretics•Aldosterone Antagonists

Spironolactone

Eplerenone

THERAPEUTIC EFFECTS

Enhances Natriuresis Caused by Other Diuretics

Blocks Aldosterone

Treatment for Primary Hyper-

aldosteronism

Prevents Hypokalemia

Used in Combination with Loop &

Thiazide Diuretics

Treatment for Edema of Liver

Cirrhosis

Treatment forHypertension

Treatment forHeart Failure

ADVERSE EFFECTS

Impotence

Gynecomastia

MetabolicAcidosis

Hyperkalemia

Hirsutism

CNS SideEffects

Peptic Ulcers

Gastritis

MenstrualIrregularities

Deepening ofVoice

OTHER EFFECTS

Nothing ofClinical

Significance

DIURETICS

How do they work?What do they do?

WHEN DO I USE THEM?How do I use them?

DEFINITION OF EDEMA

The Accumulation of AbnormalAmounts of Extravascular,

Extracellular Fluid.

ANASARCA: Severe, widelydistributed pitting edema.

TYPES OF EDEMA

LOCALIZEDGENERALIZED

•Inflammation•Lymphatic Obstruction•Venous Obstruction•Thrombophlebitis

•CARDIAC•HEPATIC•RENAL

NEPHROTIC SYNDROMEACUTE GNCRF

•IDIOPATHIC•OTHER

CyclicMyxedemaVasodilator-inducedPregnancy-inducedCapillary leak syndrome

MECHANISMS OFEDEMA FORMATION

IS

Pcapcap

PISalance of

Starling Forces

Filtration < or = Lymphatic Drainage

Filtration > Lymphatic Drainage

odema

DEMA

(Capillary Permeability)

nterstitial Space

CARDIAC EDEMADiagnosis

•History of Heart Disease•Evidence of Pulmonary Edema

•Orthopnea•SOB•Exertional Dyspnea

•Evidence of Volume Expansion•Hepatic Congestion•Hepatojugular Reflux

•Ventricular Gallop Rhythm

CARDIAC EDEMAPathophysiology

HEART DISEASE

Left VentricularDysfunction

Right VentricularDysfunction

IncreasedPulmonary

Venous Pressure

Pulmonary Edema Systemic Edema

Hypotension

Renal Na Retention

HEPATIC EDEMADiagnosis

•History of Liver Disease•Diminished CrCl (Normal Serum Cr)•Evidence of Chronic Liver Disease

•Spider Angiomata•Palmar Erythema•Jaundice•Hypoalbuminemia

•Evidence of Portal Hypertension•Venous Pattern on Abdominal Wall•Esophogeal Varices•Ascites

LIVER DISEASE

Neurohumoral Activation(Increased “Volume Hormones”)

Liver Cirrhosis

Increased Pressure in Hepatic Sinusoids

Exudation of Fluid Into Peritoneal Cavity

Systemic Edema

Ascites

Renal Na Retention

HEPATIC EDEMAPathophysiology

Functional Renal Insufficiency(Hepatorenal Syndrome)

RENAL EDEMADiagnosis

History of Renal Disease

Evidence of Albumin Loss•Narrow, pale transverse bands in nail beds•Proteinuria (3+ to 4+)•Hypoalbuminemia

Renal Imaging•Enlarged Kidneys Nephrotic Syndrome or AGN•Shrunken Kidneys CRF

RENAL EDEMADiagnosis

Nephrotic Syndrome•Hyaline Casts•Oval Fat Bodies•Lipid Droplets/Casts

Acute Glomerulonephritis•Hematuria•Erythrocyte Casts•Leukocyte Casts•Pyuria

Chronic Renal Failure•Broad Waxy Casts

Urinalysis

RENAL EDEMAPathophysiology

RENAL DISEASE

Urinary Loss of Albumin Reduced GFR

Hypoalbuminemia

Altered Starling Forces

Systemic Edema

Renal Na RetentionNEPH

ROTIC P

ATHW

AY NEPHRITIC PATHWAY

NEPHRITIC PATHWAY

CARDIAC

DependentEdema

HEPATIC RENAL

Proteinuria

Facial Edema

Ascites

Hypoalbuminemia

Severe

Absent Absent

Absent/Mild

SevereAbsent/Mild

SevereModerate/Mild

Absent

Absent/Trace

Absent/Trace

Severe/Moderate

Moderate

Mild

Severe

IDIOPATHIC EDEMADiagnosis

•Women of Childbearing Age•Associated with Eating Disorders•Dependent Edema•Facial Edema•Abdominal Bloating

IDIOPATHIC EDEMAPathophysiology

IS

Pcapcap

PISalance of

Starling Forces

Filtration > Lymphatic Drainage DEMA

(Capillary Permeability)

nterstitial Space

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

Frac

tiona

l Exc

retio

n of

So

dium

(%)

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 DistalNa Na

Proximal DistalNa

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

ChronicRenal

Failure

Nephrotic Syndrome

CirrhosisMild CHF

Moderate or

Severe CHF

Loop Diuretic: Titrate Single Daily Dose up to Ceiling Dose as Needed

Thiazide Diuretic:CrCl > 50, use 25 to 50 mg/d HCTZCrCl 20 to 50, use 50 to 100 mg/d HCTZCrCl < 20, use 100 to 200 mg/d HCTZ

K+-Sparing Diuretic:If CrCl > 75 & 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.)

Add

While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion

Spironolactone:Titrate up to 400 mg/das needed.

CrCl<50

Thiazide:50 to 100 mg/d HCTZ

CrCl>50

Cr

Cl

<5

0CrCl>50

Drop Thiazide

Add

Loop Diuretic: Increase Frequency of Ceiling Dose as Needed:Furosemide, up to 3X daily; Bumetanide, up to 4X daily; Torsemide, up to 2X daily

Add

Add

Reading Assignment

Chapter 54 – DiureticsBy Christopher S. Wilcox

In Brenner and Rector’s The Kidney

7th Edition, 2004Available online via

HSL Online Resources (Electronic Books)