University of Pittsburgh

School of Medicine
Center for Clinical Pharmacology

DIURETICS
Edwin K. Jackson, Ph.D.

DIURETICS
HOW DO THEY WORK?
What do they do?
When do I use them?
How do I use them?

RENAL
ANATOMY &
PHYSIOLOGY

Renal Circulation

Nephron

Macula
Densa

Glomerulus

Glomerular Capillaries

Nephron

Epithelial Cell

EPITHELIAL
TRANSPORT

MECHANISM
OF ACTION

Na-K-2Cl SYMPORT
INHIBITORS
Also Called:
Loop Diuretics
High Ceiling Diuretics
Ethacrynic
Acid

Furosemide
(LASIX)

(EDECRIN)

Bumetanide

Torsemide

(BUMEX)

(DEMADEX)

(Bartters Syndrome)

Na-Cl SYMPORT INHIBITORS

Also Called:
Thiazide Diuretics
Thiazide-Like Diuretics
Hydrochlorothiazide
(HYDRODIURIL)

Chlorthalidone
(HYGROTON)

Chlorothiazide

Metolazone

(DIURIL)

(ZAROXOLYN)

(Gitelmans Syndrome)

Na CHANNEL
INHIBITORS
Also Called:
K-Sparing Diuretics
Triamterene
(DYRENIUM)

Amiloride
(MIDAMOR)

(Liddles 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
Furosemide
Bumetanide

Ethacrynic
Acid
Torsemide

THERAPEUTIC EFFECTS
Increase Na Excretion
to 25% of Filtered Load

Treatment for
Severe Edema

Increase Urine Volume

Treatment for
Oliguric ARF

Increase Ca Excretion

Treatment for
Hypercalcemia

Impair Free Water

Reabsorption

Treatment for
Hyponatremia

Increase Venous
Capacitance

Treatment for
Pulmonary
Edema

ADVERSE EFFECTS
Profound ECFV
Depletion

Hypocalcemia

Hypokalemia

Ototoxicity

Metabolic
Alkalosis

Hyperuricemia

Hypomagnesemia

Hyperglycemia

OTHER EFFECTS
Release PGs

Increase Renin
Release

Block TGF

Increase &
Redistribute
RBF

Na-Cl SYMPORT INHIBITORS

Also Called:
Thiazide Diuretics
Thiazide-Like Diuretics
Hydrochlorothiazide
Chlorothiazide

Chlorthalidone
Metolazone

THERAPEUTIC EFFECTS
Increase Na Excretion
to 5% of Filtered Load

Treatment for
Mild Edema

Decrease Ca Excretion

Treatment for
Hypertension

Treatment for
Nephrogenic
Diabetes
Insipidus

Treatment for
Calcium
Nephrolithiasis

ADVERSE EFFECTS
ECFV
Depletion
Hypokalemia

Hypercalcemia
Hyponatremia

Metabolic
Alkalosis

Hyperuricemia
Hyperglycemia

Hypomagnesemia
Impotence

Increased LDL

(Renal Cell Carcinoma??)

OTHER EFFECTS

Nothing of
Clinical
Significance

Na CHANNEL
INHIBITORS
Also Called:
K-Sparing Diuretics
Triamterene
Amiloride

THERAPEUTIC EFFECTS
Enhance Natriuresis
Caused by Other Diuretics
Prevent Hypokalemia

Used in
Combination
with Loop &
Thiazide
Diuretics

Block Na Channels

Treatment for
Liddles
Syndrome

Treatment for
LithiumInduced
Diabetes
Insipidus

ADVERSE EFFECTS
Amiloride
Hyperkalemia

Triamterene
Hyperkalemia
Renal Stones
Interstitial
Nephritis
Megaloblastosis

OTHER EFFECTS

Nothing of
Clinical
Significance

MINERALOCORTICOID
RECEPTOR ANTAGONISTS
Also Called:
K-Sparing Diuretics
Aldosterone Antagonists
Spironolactone
Eplerenone

THERAPEUTIC EFFECTS
Used in
Combination
with Loop &
Thiazide
Diuretics

Enhances Natriuresis
Caused by Other Diuretics
Prevents Hypokalemia

Blocks Aldosterone

Treatment for
Primary
Hyperaldosteronism

Treatment for
Heart Failure
Treatment for
Edema of Liver
Cirrhosis

Treatment for
Hypertension

ADVERSE EFFECTS
Hyperkalemia
Metabolic
Acidosis

Gastritis
Peptic Ulcers

Deepening of
Voice

Impotence
CNS Side
Effects
Gynecomastia

Hirsutism
Menstrual
Irregularities

OTHER EFFECTS

Nothing of
Clinical
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 Abnormal
Amounts of Extravascular,
Extracellular Fluid.

ANASARCA: Severe, widely

distributed pitting edema.

TYPES OF EDEMA
GENERALIZED
LOCALIZED
Inflammation
Lymphatic Obstruction
Venous Obstruction
Thrombophlebitis

CARDIAC
HEPATIC
RENAL
NEPHROTIC SYNDROME
ACUTE GN
CRF
IDIOPATHIC
OTHER
Cyclic
Myxedema
Vasodilator-induced
Pregnancy-induced
Capillary leak syndrome

MECHANISMS OF
EDEMA FORMATION

of
e
c
n
a
l
a

rces
o
F
g
n
i
l
Sta r

P cap
IS

P IS
cap

(Capillary Permeability)
nterstitial Space
Filtration < or = Lymphatic Drainage

odema

Filtration > Lymphatic Drainage

DEMA

CARDIAC EDEMA
Diagnosis
History of Heart Disease
Evidence of Pulmonary Edema
Orthopnea
SOB
Exertional Dyspnea
Evidence of Volume Expansion
Hepatic Congestion
Hepatojugular Reflux
Ventricular Gallop Rhythm

CARDIAC EDEMA
Pathophysiology
HEART DISEASE
Left Ventricular
Dysfunction

Increased
Pulmonary
Venous Pressure

Pulmonary Edema

Right Ventricular
Dysfunction

Hypotension
Renal Na Retention
Systemic Edema

HEPATIC EDEMA
Diagnosis
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
Liver Cirrhosis

HEPATIC EDEMA
Pathophysiology

Increased Pressure in Hepatic Sinusoids

Exudation of Fluid Into Peritoneal Cavity

Ascites

Neurohumoral Activation
(Increased Volume Hormones)

Functional Renal Insufficiency

(Hepatorenal Syndrome)

Renal Na Retention

Systemic Edema

RENAL EDEMA
Diagnosis
History of Renal Disease
Evidence of Albumin Loss
Narrow, pale transverse bands in nail beds
Proteinuria (3+ to 4+)
Hypoalbuminemia

Renal Imaging
Enlarged Kidneys
Shrunken Kidneys

Nephrotic Syndrome or AGN

CRF

RENAL EDEMA
Diagnosis

Urinalysis

Nephrotic Syndrome
Hyaline Casts
Oval Fat Bodies
Lipid Droplets/Casts
Acute Glomerulonephritis
Hematuria
Erythrocyte Casts
Leukocyte Casts
Pyuria
Chronic Renal Failure
Broad Waxy Casts

C
RO
TI

Urinary Loss of Albumin

Reduced GFR

Hypoalbuminemia

Renal Na Retention

Altered Starling Forces

Systemic Edema

AY
W
TH
PA

NE
PH

RENAL DISEASE

C
TI
RI
PH
NE

PA
TH
W
AY

RENAL EDEMA
Pathophysiology

CARDIAC
Dependent
Edema
Facial Edema
Ascites
Hypoalbuminemia
Proteinuria

Severe
Absent

HEPATIC

RENAL

Moderat
Mil
e
d
Absent Severe/Moderate

Absent/Mil
Severe
Absent/Mil
d
d
Absent
Moderate/Mil
Severe
d
Absent/Trace
Absent/Trace
Severe

IDIOPATHIC EDEMA
Diagnosis

Women of Childbearing Age

Associated with Eating Disorders
Dependent Edema
Facial Edema
Abdominal Bloating

IDIOPATHIC EDEMA
Pathophysiology

of
e
c
n
a
l
a

rces
o
F
g
n
i
l
Sta r

P cap
IS

P IS
cap

(Capillary Permeability)
nterstitial Space

Filtration > Lymphatic Drainage

DEMA

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
Sodium (%)

e
s 150
n
o
p 100
s
e 50
R
0

0.01

Ceiling Effect

Ceiling [Diuretic]TL
0.1

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%

Torsemide

~ 100%

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

Na
Acute
Loop

Chronic
Loop

Chronic
Loop +
Thiazide

Proximal

Na

Proximal

Distal
Na

Distal

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 to 2

0.5 to 1

0.5

Torsemide

20

10 to 20

5 to 10

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

Chronic
Renal
Failure

Nephrotic
Syndrome

Moderate
or
Severe
CHF

Cirrhosis

Mild CHF

Spironolactone:
Titrate up to 400 mg/d
as needed.
CrCl<
50
Add

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

Cr
Cl
>

C
rC
50 l<

50

CrCl>
50

Add

Drop Thiazide

Thiazide:
50 to 100 mg/d HCTZ

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

K+-Sparing Diuretic:
Thiazide Diuretic:
If CrCl > 75 & urinary [Na]:[K] ratio is < 1
CrCl > 50, use 25 to 50 mg/d HCTZ
(Note: May add K-Sparing Diuretic to Loop
Add
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

Reading Assignment
Chapter 54 Diuretics
By Christopher S. Wilcox
In
Brenner and Rectors The Kidney
7th Edition, 2004
Available online via
HSL Online Resources (Electronic Books)