DIURETICS

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DIURETICS
University of Pittsburgh School of
Medicine Center for Clinical Pharmacology
Edwin K. Jackson, Ph.D.
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DIURETICS
HOW DO THEY WORK? What do they do? When do I use
them? How do I use them?
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RENAL ANATOMY PHYSIOLOGY
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Renal Circulation
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Nephron
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Macula Densa
Glomerulus
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Glomerular Capillaries
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Nephron
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Epithelial Cell
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EPITHELIAL TRANSPORT
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MECHANISM OF ACTION
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Na-K-2Cl SYMPORT INHIBITORS

• Also Called
• Loop Diuretics
• High Ceiling Diuretics

Ethacrynic Acid (EDECRIN)
Furosemide (LASIX)
Torsemide (DEMADEX)
Bumetanide (BUMEX)
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(Bartters Syndrome)
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Na-Cl SYMPORT INHIBITORS

• Also Called
• Thiazide Diuretics
• Thiazide-Like Diuretics

Chlorthalidone (HYGROTON)
Hydrochlorothiazide (HYDRODIURIL)
Metolazone (ZAROXOLYN)
Chlorothiazide (DIURIL)
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(Gitelmans Syndrome)
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Na CHANNELINHIBITORS

• Also Called
• K-Sparing Diuretics

Triamterene (DYRENIUM)
Amiloride (MIDAMOR)
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(Liddles Syndrome)
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MINERALOCORTICOID RECEPTOR ANTAGONISTS

• Also Called
• K-Sparing Diuretics
• Aldosterone Antagonists

Spironolactone (ALDACTONE)
Eplerenone (INSPRA)
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(Syndrome of Apparent MC excess)
(Licorice Glycyrrhizic Acid)
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DIURETICS
How do they work? WHAT DO THEY DO? When do I use
them? How do I use them?
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Na-K-2Cl SYMPORT INHIBITORS

• Also Called
• Loop Diuretics
• High Ceiling Diuretics

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THERAPEUTIC EFFECTS
Treatment for Severe Edema
Increase Na Excretion to 25 of Filtered Load
Treatment for Oliguric ARF
Increase Urine Volume
Treatment for Hypercalcemia
Increase Ca Excretion
Treatment for Hyponatremia
Impair Free Water Reabsorption
Treatment for Pulmonary Edema
Increase Venous Capacitance
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ADVERSE EFFECTS
Profound ECFV Depletion
Hypocalcemia
Hypokalemia
Ototoxicity
Metabolic Alkalosis
Hyperuricemia
Hypomagnesemia
Hyperglycemia
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OTHER EFFECTS
Block TGF
Release PGs
Increase Redistribute RBF
Increase Renin Release
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Na-Cl SYMPORT INHIBITORS

• Also Called
• Thiazide Diuretics
• Thiazide-Like Diuretics

Hydrochlorothiazide
Chlorthalidone
Metolazone
Chlorothiazide
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THERAPEUTIC EFFECTS
Increase Na Excretion to 5 of Filtered Load
Treatment for Nephrogenic Diabetes Insipidus
Treatment for Hypertension
Treatment for Mild Edema
Treatment for Calcium Nephrolithiasis
Decrease Ca Excretion
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ADVERSE EFFECTS
Hypercalcemia
ECFV Depletion
Hypokalemia
Hyponatremia
Hyperuricemia
Metabolic Alkalosis
Hypomagnesemia
Hyperglycemia
Impotence
Increased LDL
(Renal Cell Carcinoma??)
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OTHER EFFECTS
Nothing of Clinical Significance
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Na CHANNELINHIBITORS

• Also Called
• K-Sparing Diuretics

Triamterene
Amiloride
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THERAPEUTIC EFFECTS
Used in Combination with Loop Thiazide Diuretics
Enhance Natriuresis Caused by Other Diuretics
Prevent Hypokalemia
Block Na Channels
Treatment for Lithium-Induced Diabetes Insipidus
Treatment for Liddles Syndrome
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ADVERSE EFFECTS
Triamterene
Amiloride
Hyperkalemia
Hyperkalemia
Renal Stones
Interstitial Nephritis
Megaloblastosis
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OTHER EFFECTS
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MINERALOCORTICOID RECEPTOR ANTAGONISTS

• Also Called
• K-Sparing Diuretics
• Aldosterone Antagonists

Spironolactone
Eplerenone
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THERAPEUTIC EFFECTS
Used in Combination with Loop Thiazide Diuretics
Enhances Natriuresis Caused by Other Diuretics
Prevents Hypokalemia
Blocks Aldosterone
Treatment for Primary Hyper-aldosteronism
Treatment for Heart Failure
Treatment for Edema of Liver Cirrhosis
Treatment for Hypertension
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ADVERSE EFFECTS
Gastritis
Hyperkalemia
Peptic Ulcers
Metabolic Acidosis
Impotence
Deepening of Voice
CNS Side Effects
Hirsutism
Gynecomastia
Menstrual Irregularities
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OTHER EFFECTS
Nothing of Clinical Significance
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DIURETICS
How do they work? What do they do? WHEN DO I USE
THEM? How do I use them?
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DEFINITION OF EDEMA
The Accumulation of Abnormal Amounts of
Extravascular, Extracellular Fluid.
ANASARCA Severe, widely distributed pitting
edema.
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TYPES OF EDEMA
GENERALIZED
LOCALIZED

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

• Inflammation
• Lymphatic Obstruction
• Venous Obstruction
• Thrombophlebitis

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MECHANISMS OF EDEMA FORMATION
PIS
?alance of Starling Forces
?cap
Pcap
?IS
(Capillary Permeability)
?nterstitial Space
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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

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CARDIAC EDEMA Pathophysiology
HEART DISEASE
Left Ventricular Dysfunction
Right Ventricular Dysfunction
Hypotension
Increased Pulmonary Venous Pressure
Renal Na Retention
Pulmonary Edema
Systemic Edema
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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

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LIVER DISEASE
HEPATIC EDEMA Pathophysiology
Liver Cirrhosis
Increased Pressure in Hepatic Sinusoids
Neurohumoral Activation (Increased Volume
Hormones)
Exudation of Fluid Into Peritoneal Cavity
Functional Renal Insufficiency (Hepatorenal
Syndrome)
Ascites
Renal Na Retention
Systemic Edema
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RENAL EDEMA Diagnosis
History of Renal Disease

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

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

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RENAL EDEMA Diagnosis

• 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
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RENAL EDEMA Pathophysiology
RENAL DISEASE
NEPHRITIC PATHWAY
NEPHROTIC PATHWAY
Reduced GFR
Urinary Loss of Albumin
Hypoalbuminemia
Renal Na Retention
Altered Starling Forces
Systemic Edema
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CARDIAC
HEPATIC
RENAL
Dependent Edema
Severe
Moderate
Mild
Facial Edema
Absent
Absent
Severe/Moderate
Ascites
Absent/Mild
Severe
Absent/Mild
Hypoalbuminemia
Severe
Moderate/Mild
Absent
Proteinuria
Absent/Trace
Severe
Absent/Trace
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IDIOPATHIC EDEMA Diagnosis

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

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IDIOPATHIC EDEMA Pathophysiology
PIS
?alance of Starling Forces
?
?cap
Pcap
?
?IS
?
(Capillary Permeability)
?nterstitial Space
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DIURETICS
How do they work? What do they do? When do I use
them? HOW DO I USE THEM?
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CONCEPT OF CEILING DOSE
Ceiling Effect
Fractional Excretion of Sodium ()
Ceiling DiureticTL
Log DiureticTL
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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 Diuret
ic Response.
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CONCEPT OF CEILING DOSE
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CONCEPT OF CEILING DOSE
Pointless, and possibly harmful, to exceed
ceiling dose of diuretic!!
Exceeding Ceiling Dose Yields
No Additional Effect
Possible Adverse Effects
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DETERMINANTS OF CEILING DOSE

• Ceiling Dose Depends on
• Diuretic
• Disease

VARIABLE
CEILING DOSE
Decrease
Increased Potency
Decreased Tubular Transport (e.g., ARF/CRF)
Increase
Increased Binding to Urinary Proteins (e.g.,
Nephrotic Syndrome)
Increase
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CEILING DOSES FOR I.V. LOOP DIURETICS (in mgs)
NEPHROTIC SYNDROME
AFR/CRF Moderate
AFR/CRF Severe
CIRRHOSIS
HEART FAILURE
40 to 80
160 to 200
80 to 160
80 to 120
40 to 80
Furosemide
1 to 2
8 to 10
4 to 8
2 to 3
1 to 2
Bumetanide
10 to 20
50 to 100
20 to 50
20 to 50
10 to 20
Torsemide
Protein Binding Increases Ceiling Dose
Impaired Delivery Increases Ceiling Dose
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CONVERTING I.V. DOSING TO ORAL DOSING
BIOAVAILABILITY
CONVERSION FACTOR
50 (highly variable)
2 or higher
Furosemide
Bumetanide
100
1
Torsemide
100
1
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DETERMINANTS OF CEILING EFFECT

• Ceiling Effect Depends on
• Diuretic
• Disease

VARIABLE
CEILING EFFECT
Loop gt Thiazide gt K-Sparing
Diuretic
Diminished Nephron Response in Nephrotic
Syndrome, Cirrhosis, Heart Failure.
Disease
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MECHANISMS OF DIURETIC RESISTANCE
MECHANISM
SOLUTION
Patient Counseling
Noncompliance
Patient Counseling
NSAIDS
Decreased Tubular Transport (e.g., ARF CRF)
Push to Ceiling Dose
Bed Rest
Decreased RBF
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MECHANISMS OF DIURETIC RESISTANCE (Continued)
MECHANISM
SOLUTION
Changes in Volume Hormones (SNS, RAS, ADH ANF)
Bed Rest
Combination Therapy (Sequential Blockade)
Compensation by Distal Nephron
Diminished Nephron Response (CHF, Cirrhosis,
Nephrotic Syndrome)
More Frequent Dosing or Continuous Infusion
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MECHANISMS OF DIURETIC RESISTANCE
Proximal
Distal
Na
Na
Proximal
Distal
Na
Acute Loop
Na
Distal
Proximal
Chronic Loop
Na
Na
Distal
Proximal
Chronic Loop Thiazide
Na
Na
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MECHANISMS OF DIURETIC RESISTANCE (Continued)
MECHANISM
SOLUTION
Changes in Volume Hormones (SNS, RAS, ADH ANF)
Bed Rest
Combination Therapy (Sequential Blockade)
Compensation by Distal Nephron
Diminished Nephron Response (CHF, Cirrhosis,
Nephrotic Syndrome)
More Frequent Dosing or Continuous Infusion
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RATIONALE FOR MORE FREQUENT DOSING OR CONTINUOUS
I.V. INFUSION
DiureticTL
Ceiling
DiureticTL
Ceiling
DiureticTL
Ceiling
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CEILING DOSES FOR CONTINUOUS I.V. INFUSION OF
LOOP DIURETICS (in mgs per hour)
LOADING DOSE (in mgs)
CrCl lt 25
CrCl 25 to 75
CrCl gt 75
10
10 to 20
20 to 40
40
Furosemide
1
Bumetanide
0.5
0.5 to 1
1 to 2
5
5 to 10
10 to 20
20
Torsemide
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WHAT HAPPENS WHEN DIURETIC IN TUBULAR LUMEN IS
LESS THAN CEILING??
Postdiuresis Sodium Retention!!
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RATIONALE FOR LOW SODIUM DIET
A low sodium diet attenuates postdiuretic sodium
retention, thereby lowering diuretic requirements!
!
Major Problem is Compliance
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IMPORTANT DRUG INTERACTIONS
NSAIDS Salt Decongestants Probenecid
Diminished Diuretic Response
Hyperkalemia- Induced by K-Sparing Diuretics
ACE Inhibitors Beta-Blockers K Supplements K-Spari
ng Diuretics Heparin
Enhanced Ototoxicity of Loop Diuretic
Ototoxic Drugs
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Severe/Moderate CHF
ARF/CRF
Nephrotic Syndrome
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 Thiazide
• If CrCl gt 50
• 50 to 100 mg/d HCTZ

• ADD K-Sparing Diuretic
• If CrCl gt 75
• If Urinary NaK ratio is lt 1
• (Note May add K-Sparing Diuretic to Loop
• and/or Thiazide Diuretic at Any Point in
  Algorithm
• for K Homeostasis.)

• ADD Thiazide Diuretic
• CrCl gt 50, use 25 to 50 mg/d HCTZ
• CrCl 20 to 50, use 50 to 100 mg/d HCTZ
• CrCl lt 20, use 100 to 200 mg/d HCTZ

While Maintaining Other Diuretics, Switch Loop
Agent to Continuous Infusion
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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)