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Pharmacy Pharmacology:

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+ flows down concentration gradient


• Na/K ATPase maintains gradient
• Water follows passively
• 67% of Na and water reabsorption
Loop of Henle
• TDL permeable to water but not
Na+
• TAL impermeable to water and
transports Na+
• Differences in permeabilities
creates the countercurrent
multiplier
• Countercurrent multiplier creates
interstitial osmolar gradient
• 20% of filtered load of Na absorbed
by the TAL
Distal Convoluted Tubule

• 5% of filtered load of Na+


reabsorbed
• Segment mostly impermeable to
water
Cortical Collecting Duct
• Water permeability controlled by
antidiuretic hormone (ADH)
• Driving force for water
reabsorption is created by the
countercurrent multiplier
• 2-3% of filtered Na+ reabsorbed
here via Na+ channels that are
regulated by aldosterone
• Major site of K+ secretion
Classes of Diuretics:
Definitions
• Diuretic: substance that promotes the
excretion of urine
• Natriuretic: substance that promotes
the renal excretion of sodium
Objective 2
Discuss the chemical
characteristics,
pharmacological
properties, therapeutics
uses and adverse
effects of the thiazide
and thiazide-like
diuretics
Mechanism
of 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”
Increased K+ Excretion Due To:
• Increased urine flow per se
• Increased Na+-K+ exchange
• Increased aldosterone release

Na+/K+ exchange
in the cortical
collecting duct
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
Pharmacokinetics
• Oral administration - absorption poor
• Diuresis within one hour
• T1/2 for chlorothiazide is 1.5 hours,
chlorthalidone 44 hours
• Bo-
• Ring
Therapeutic Uses

• Edema due to CHF (mild to moderate)


• Essential hypertension
• Diabetes insipidus
• Hypercalciuria
Diabetes Insipidus
• Thiazides: paradoxical reduction in
urine volume
• Mechanism: volume depletion causes
decreased GFR
• Treatment of Li+ toxicity:
– Thiazides useful
– Li+ reabsorption increased by thiazides.
Reduce Li dosage by 50%
Thiazide Use in Hypercalciuria -
Recurrent Ca2+ Calculi
• Thiazides promote
distal tubular Ca2+
reabsorption
• Prevent “excess”
excretion which could
form stones in the
ducts of the kidney
• 50-100 mg HCT kept
most patients stone
free for three years of
follow-up in a recent
study
Thiazide Toxicity
• Hypokalemia due to:
– Increased availability of Na+ for exchange at
collecting 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
Objective 3
Discuss the chemical
characteristics, pharmacological
properties, therapeutics uses
and adverse effects of the
“loop” diuretics
Available Loop
Diuretics
• Furosemide
(prototype)
• Bumetanide
• Torsemide
• Ethacrynic acid
Molecular Mechanism of Action

• 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

Discuss the chemical


characteristics, pharmacological
properties, therapeutics uses
and adverse effects of the
carbonic anhydrase inhibitors
Prototype: Acetazolamide

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

• Osmotic diuretics are still filtered under these


conditions and retain an equivalent amount of
water, maintaining urine flow
Therapeutic Uses (Cont.)
Reduction of pressure in extravascular fluid
compartments

• Reduction of CSF pressure and


volume
• Reduction of intraocular pressure
Toxicity of Osmotic Diuretics
• Increased extracellular fluid volume
• Hypersensitivity reactions
• Glycerin metabolism can lead to
hyperglycemia and glycosuria
• Headache, nausea and vomiting
Summary: Sites of Diuretic Action