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Pharmacy Pharmacology:
Diuretics Instructor:
William B. Jeffries, [email protected]
flap.creighton.edu
Required Reading:
Katzung, Chapter 15
http://flap.creighton.edu/http://www.usrf.org/mannekin.htmlhttp://flap.creighton.edu/http://flap.creighton.edu/http://flap.creighton.edu/http://flap.creighton.edu/8/14/2019 Pharmacy Diuretics
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Objective 1
Review the pathways of Na+ and
water reabsorption along the
human nephron
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Nephro
nStructure
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Renal Epithelial Cell Polarity DrivesNa+ and Water Transport
TubularFluid Blood
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Proximal Tubule
Na+ flows down concentration gradient
Na/K ATPase maintains gradient
Water follows passively 67% of Na and water reabsorption
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Loop of Henle
TDL permeable to water but notNa+
TAL impermeable to water andtransports Na+
Differences in permeabilitiescreates the countercurrentmultiplier
Countercurrent multiplier createsinterstitial osmolar gradient
20% of filtered load of Na absorbed
by the TAL
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Distal Convoluted Tubule
5% of filtered load of Na+reabsorbed
Segment mostly impermeable towater
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Cortical Collecting Duct
Water permeability controlled byantidiuretic hormone (ADH)
Driving force for water
reabsorption is created by thecountercurrent multiplier
2-3% of filtered Na+ reabsorbed
here via Na+
channels that areregulated by aldosterone
Major site of K+ secretion
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Classes of Diuretics:
Definitions Diuretic: substance that promotes the
excretion of urine Natriuretic: substance that promotes
the renal excretion of sodium
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Objective 2
Discuss the chemical
characteristics,
pharmacological
properties, therapeuticsuses and adverse
effects of the thiazide
and thiazide-like
diuretics
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Mechanismof Action
Thiazides freely filtered and secreted in proximal tubule
Bind to the electroneutral NaCl cotransporter
Thiazides impair Na+ and Cl- reabsorption in the early
distal tubule: low ceiling
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Increased K+ Excretion Due To:
Increased urine flow per se Increased Na+-K+ exchange
Increased aldosterone release
Na+/K+ exchange
in the corticalcollecting duct
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Whole Body Effects of Thiazides
Increased urinary excretion of:
Na+
Cl-
K+
Water
HCO3- (dependent on structure)
Reduced ECF volume (contraction)
Reduce blood pressure (lower CO)
Reduced GFR
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Pharmacokinetics
Oral administration - absorption poor
Diuresis within one hour
T1/2 for chlorothiazide is 1.5 hours,chlorthalidone 44 hours
Bo-
Ring
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Therapeutic Uses
Edema due to CHF (mild to moderate)
Essential hypertension
Diabetes insipidus
Hypercalciuria
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Diabetes Insipidus
Thiazides: paradoxical reduction inurine volume
Mechanism: volume depletion causes
decreased GFR Treatment of Li+ toxicity:
Thiazides useful
Li+ reabsorption increased by thiazides.Reduce Li dosage by 50%
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Thiazide Use in Hypercalciuria -
Recurrent Ca2+ Calculi Thiazides promote
distal tubular Ca2+reabsorption
Prevent excessexcretion which couldform stones in theducts of the kidney
50-100 mg HCT keptmost patients stonefree for three years offollow-up in a recentstudy
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Thiazide Toxicity Hypokalemia due to:
Increased availability of Na+ for exchange atcollecting duct
Volume contraction induced aldosterone release
Hyperuricemia Direct competition of thiazides for urate transport
Enhanced proximal tubular reabsorption efficiency
Hyperglycemia Diminished insulin secretion Related to the fall in serum K+
Elevated plasma lipids
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Objective 3
Discuss the chemical
characteristics, pharmacological
properties, therapeutics usesand adverse effects of the
loop diuretics
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Available Loop
Diuretics
Furosemide
(prototype)
Bumetanide
Torsemide
Ethacrynic acid
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Molecular Mechanism of Action
Enter proximal
tubule via organic
acid transporter
Inhibition of theapical Na-K-2Cl
cotransporter of
the TALH
Competition withCl- ion for binding
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Pharmacological Effects of
Loop Diuretics Loss of diluting ability: Increased Na, Cl andK excretion
Loss of concentrating ability:
reduction in the medullary osmotic gradient
Loss in ADH-directed water reabsorption incollecting ducts
Loss of TAL electrostatic driving force:
increased excretion of Ca2+, Mg2+ and NH4+
Increased electrostatic driving force in CCD:increased K+ and H+ excretion
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Pharmacokinetics
Rapid oral absorption, bioavailabilityranges from 65-100%
Rapid onset of action
extensively bound to plasma proteins secreted by proximal tubule organicacid transporters
Blah
Blah
Blah
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Therapeutic Uses
Edema of cardiac, hepatic or renalorigin
Acute pulmonary edema (parenteral
route) Chronic renal failure or nephrosis
Hypertension
Symptomatic hypercalcemia
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Loop Diuretic Toxicity
Hypokalemia
Magnesium depletion
Chronic dilutional hyponatremia
Metabolic alkalosis
Hyperuricemia
Ototoxicity
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Drug Interactions Displacement of plasma protein binding of
clofibrate and warfarin
Li+ clearance is decreased
Loop diuretics increase renal toxicity of
cephalosporin antibiotics
Additive toxicity w/ other ototoxic drugs
Inhibitors of organic acid transport
(probenecid, NSAID's) shift the dose-response curve of loop diuretics to the right
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Objective 4
Discuss the chemicalcharacteristics,pharmacological
properties, therapeuticsuses and adverse effectsof the potassium-sparing diuretics
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Spironolactone Mechanism of
action: aldosterone
antagonist
Aldosterone receptor
function Spironolactone
prevents conversion
of the receptor to
active form, thereby
preventing the actionof aldosterone
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Therapeutic Uses
Prevent K loss caused by otherdiuretics in:
Hypertension
Refractory edema Heart failure
Primary aldosteronism
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Administration
Dose orally administered (100 mg/day)
Spironolactone/thiazide prep
(aldactazide, 25 or 50 mg of each drugin equal ratio)
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Toxicity
Hyperkalemia - avoid excessive Ksupplementation when patient is on
spironolactone
Androgen like effects due to it steroidstructure
Gynecomastia
GI disturbances
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Triamterene and Amiloride
Non-steroid in
structure, not
aldosterone
antagonists
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Mechanism of Action Blockade of apical Na+
channel in the principal
cells of the CCD
Amiloride: blocks the Na/H
exchanger (higher
concentrations)
Blockade of the
electrogenic entry of
sodium causes a drop in
apical membrane potential(less negative), which is the
driving force for K+
secretion
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Pharmacokinetics Triamterine
50% absorption of oral dose
60% bound to plasma proteins
Extensive hepatic metabolism with activemetabolites
Secreted by proximal tubule via organic cationtransporters
Amiloride 50% absorption of oral dose
not bound to plasma proteins not metabolized, excreted in urine unchanged
Secreted by proximal tubular cation transporters
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Therapeutic uses
Eliminate K wasting effects of
other diuretics in:
Edema
Hypertension
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Toxicity
Hyperkalemia. Avoid K+ supplementation Drug interaction - do not use in combination
with spironolactone since the potassium
sparing effect is greater than additive
Caution with ACE inhibitors
Reversible azotemia (triamterine)
Triamterene nephrolithiasis. 1 in 1500
patients
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Objective 5
Discuss the chemicalcharacteristics, pharmacologicalproperties, therapeutics usesand adverse effects of thecarbonic anhydrase inhibitors
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Prototype: Acetazolamide
Developed from
sulfanilamide, after
it was noticed thatsulfanilamide
caused metabolic
acidosis and
alkaline urine.
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Mechanism of Action: Na+
Bicarbonate Diuresis
Inhibit carbonic anhydrase in proximal tubule
Blocks reabsorption of bicarbonate ion,
preventing Na/H exchange Pharmacological effect
Sodium bicarbonate diuresis
metabolic acidosis
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Therapeutic Uses
Urinary alkalinization
Metabolic alkalosis
Glaucoma: acetazolamide,dorzalamide
Acute mountain sickness
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Objective 6
Discuss the chemical
characteristics, pharmacological
properties, therapeutics usesand adverse effects of the
osmotic diuretics
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Mechanism of Action:Inhibition of Water Diffusion
Free filtration in osmotically active
concentration
Osmotic pressure of non-reabsorbablesolute prevents water reabsorption and
increase urine volume
Proximal tubule Thin limb of the loop of Henle
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Osmotic Diuretics in Current Use
Mannitol (prototype)
Urea
Glycerin
Isosorbide
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Therapeutic Uses
Prophylaxis of renal failureMechanism:
Drastic reductions in GFR cause dramatically
increased proximal tubular water reabsorption
and a large drop in urinary excretion
Osmotic diuretics are still filtered under these
conditions and retain an equivalent amount of
water, maintaining urine flow
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Reduction of CSF pressure andvolume
Reduction of intraocular pressure
Therapeutic Uses (Cont.)
Reduction of pressure in extravascular fluidcompartments
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Toxicity of Osmotic Diuretics
Increased extracellular fluid volume
Hypersensitivity reactions
Glycerin metabolism can lead to
hyperglycemia and glycosuria Headache, nausea and vomiting
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Summary: Sites of Diuretic Action
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