pharmacology of diuretics
DESCRIPTION
diureticsTRANSCRIPT
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)