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Diuretics
• Instructor:
William B. Jeffries, Ph.D.
wbjeff@creighton.edu
flap.creighton.edu
• Required Reading:
Katzung, Chapter 15
Lecture Topics
You need to know these things:
• Mechanism of action
• Clinical indications
• Toxicity/adverse reactions
Objective 1
Review the pathways of Na+ and
water reabsorption along the
human nephron
Nephro
n
Structur
e
Renal Epithelial Cell Polarity Drives
Na+ and Water Transport
Tubular Blood
Fluid
Proximal Tubule
Na+/K+ exchange
in the cortical
collecting duct
Whole Body Effects of Thiazides
• Enter proximal
tubule via organic
acid transporter
• Inhibition of the
apical Na-K-2Cl
cotransporter of
the TALH
• Competition with
Cl- ion for binding
Pharmacological Effects of
Loop Diuretics
• Loss of diluting ability: Increased Na, Cl and
K excretion
• Loss of concentrating ability:
– reduction in the medullary osmotic gradient
– Loss in ADH-directed water reabsorption in
collecting 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
Pharmacokinetics
• Rapid oral absorption, bioavailability
ranges from 65-100%
• Rapid onset of action
• extensively bound to plasma proteins
• secreted by proximal tubule organic
acid transporters
• Blah
• Blah
• Blah
Therapeutic Uses
• Edema of cardiac, hepatic or renal
origin
• Acute pulmonary edema – (parenteral
route)
• Chronic renal failure or nephrosis
• Hypertension
• Symptomatic hypercalcemia
Loop Diuretic Toxicity
• Hypokalemia
• Magnesium depletion
• Chronic dilutional hyponatremia
• Metabolic alkalosis
• Hyperuricemia
• Ototoxicity
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
Objective 4
Discuss the chemical
characteristics,
pharmacological
properties, therapeutics
uses and adverse effects
of the “potassium-
sparing” diuretics
Spironolactone
• Mechanism of
action: aldosterone
antagonist
• Aldosterone receptor
function
• Spironolactone
prevents conversion
of the receptor to
active form, thereby
preventing the action
of aldosterone
Pharmacokinetics
• 70% absorption in GI tract
• Extensive first pass effect in liver and
enterohepatic circulation
• Extensively bound to plasma proteins
• 100% metabolites in urine
• Active metabolite: canrenone (active)
• Canrenoate (converted to canrenone)
Therapeutic Uses
• Prevent K loss caused by other
diuretics in:
– Hypertension
– Refractory edema
– Heart failure
• Primary aldosteronism
Administration
• Dose orally administered (100 mg/day)
• Spironolactone/thiazide prep
(aldactazide, 25 or 50 mg of each drug
in equal ratio)
Toxicity
• Hyperkalemia - avoid excessive K
supplementation when patient is on
spironolactone
• Androgen like effects due to it steroid
structure
• Gynecomastia
• GI disturbances
Triamterene and Amiloride
• Non-steroid in
structure, not
aldosterone
antagonists
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
Pharmacokinetics
• Triamterine
– 50% absorption of oral dose
– 60% bound to plasma proteins
– Extensive hepatic metabolism with active
metabolites
– Secreted by proximal tubule via organic cation
transporters
• Amiloride
– 50% absorption of oral dose
– not bound to plasma proteins
– not metabolized, excreted in urine unchanged
– Secreted by proximal tubular cation transporters
Therapeutic uses
• Eliminate K wasting effects of
other diuretics in:
– Edema
– Hypertension
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
Objective 5
Developed from
sulfanilamide, after
it was noticed that
sulfanilamide
caused metabolic
acidosis and
alkaline urine.
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
Therapeutic Uses
• Urinary alkalinization
• Metabolic alkalosis
• Glaucoma: acetazolamide,
dorzalamide
• Acute mountain sickness
CA Inhibitor Toxicity
• Hyperchloremic metabolic
acidosis
• Nephrolithiasis: renal stones
• Potassium wasting
Objective 6
Discuss the chemical
characteristics, pharmacological
properties, therapeutics uses
and adverse effects of the
osmotic diuretics
Osmotic Diuretic
Characteristics
• Freely filterable
• Little or no tubular reabsorption
• Inert or non-reactive
• Resistant to degradation by
tubules
Mechanism of Action:
Inhibition of Water Diffusion
• Free filtration in osmotically active
concentration
• Osmotic pressure of non-reabsorbable
solute prevents water reabsorption and
increase urine volume
– Proximal tubule
– Thin limb of the loop of Henle
Osmotic Diuretics in Current Use
• Mannitol (prototype)
• Urea
• Glycerin
• Isosorbide
Therapeutic Uses
Prophylaxis of renal failure
Mechanism:
• Drastic reductions in GFR cause dramatically
increased proximal tubular water reabsorption
and a large drop in urinary excretion