Pharmacology of Diuretics

Carmen Chungunco, MD FPCP FPCC

August 17, 2010

Objectives
Describe the actions of the major classes of
diuretics on the formation of urine and the
excretion of sodium, potassium, and other
cations
Explain the therapeutic indications, efficacy
and side effects of the major classes of
diuretics
Discuss the clinical uses of diuretics

Nephron
Structure

Proximal Tubule
Main site of
reabsorption: 85%
NaHCO3, 40% NaCl, 60%
H20, all filtered organic
solutes
Na+ flows down
concentration gradient,
water follows passively
Na/K ATPase maintains
gradient
Organic acids secretory
system

Loop of Henle
TDL permeable to water
but not Na+
TAL impermeable to water
and transports Na, 2035% reabsorbed
Hypertonic medullary
interstitium
differences in
permeabilities creates the
countercurrent multiplier
Lumen-positive electrical
potential (K) = driving
force for Mg, Ca
reabsorption

Distal Convoluted Tubule

5-10% of filtered load
of Na+ reabsorbed
Segment mostly
impermeable to water
Electrically neutral
Na/Cl transport
Ca++ actively
reabsorbed (regulated
by PTH)

Cortical Collecting Duct

2-5% of filtered Na+
reabsorbed here via Na+
channels that are
regulated by aldosterone,
determines final Na
concentration of urine
Water permeability
controlled by antidiuretic
hormone (ADH)

Cortical Collecting Duct

Major site of K secretion
Impt relation btw Na
delivery to CCD and K
secretion
Increased HCO3 w/c
cannot be reabsorbed like
Cl will also enhance K
secretion

Diuretics: Definitions
Diuretic: substance that promotes
the excretion of urine
Natriuretic: substance that
promotes the renal excretion of
sodium

Classes of Diuretics
Carbonic anhydrase inhibitors
Loop diuretics
Thiazides
K-sparing diuretics (Aldosterone antagonists)
Osmotic diuretics

Classes of Diuretics: Site of Action

Carbonic Anhydrase Inhibitors

Prototype: Acetazolamide
Blocks carbonic anhydrase
activity in the proximal
tubule
Blocks NaHCO3 reabsorption
Causes NaHCO3 diuresis
Sulfonamide group = essential
for activity

Carbonic Anhydrase Inhibitors

Well absorbed orally
Effects seen within 30 mins, peaks at 2 hours
and lasts 12 hours
Renal excretion
Actions:
Inhibits 85% of HCO3 reabsorptive capacity at
the proximal tubule (45% of whole body HCO3
reabsorption)

Acetazolamide: Clinical Uses

Glaucoma most common indication
Decreases rate of aqueous humor production,
decreasing intraocular pressure

Urinary Alkalinization
Enhanced secretion of uric acid and cystine

Contraindication:
Avoided in hepatic cirrhosis (may cause
hepatic encephalopathy)

Acetazolamide: Toxicity
Hyperchloremic Metabolic Acidosis
HCO3 wasting limits diuretic effect to 2-3
days

Renal Stones
Hypercalciuria and phosphaturia
Calcium salts unstable in alkaline urine

Potassium Wasting
NaHCO3 in the collecting tubule increases
lumen negative electrical potential thus
enhancing K+ excretion

Loop Diuretics
Furosemide
(prototype)
Bumetanide
Torsemide
Ethacrynic acid

Loop Diuretics: MOA

inhibits Na/K/2Cl
transport system in
TALH
reduces NaCl
reabsorption
reduces normal
lumen-positive
potential causing
increased Mg++ and
Ca++ excretion

Loop Diuretics : Pharmacological

Effects
Loss of diluting ability: Increased Na, Cl and
K excretion
Loss of concentrating ability:
reduction in the medullary osmotic
gradient
Loss of TAL electrostatic driving force:
increased excretion of Ca2+, Mg2+ and NH4+
Increased electrostatic driving force in CCD:
increased K+ and H+ excretion

Loop Diuretics: Pharmacokinetics

Rapid oral absorption, bioavailability ranges
from 65-100%
Rapid onset of action (within minutes, lasts 2-3
hours)
extensively bound to plasma proteins
secreted by proximal tubule organic acid
transporters

Loop Diuretics: Clinical Uses

Edema of cardiac, hepatic or renal origin
Acute pulmonary edema (parenteral route)
Most important indications

Chronic renal failure

Increases rate of urine flow

Hyperkalemia
Symptomatic hypercalcemia

Loop Diuretics: Toxicity

Hypokalemia
Magnesium depletion
Chronic dilutional hyponatremia
Metabolic alkalosis
Hyperuricemia
Hypovolemia-associated enhancement of uric acid
reabsorption in proximal tubule

Ototoxicity
Dose-related

Thiazides
Contain sulfonamide
group
Chlorothiazide
Chlorthalidone
Indapamide

Thiazides: MOA

inhibit NaCl reabsorption in distal convoluted

tubule
enhance Ca++ reabsorption (modulated by PTH)

Thiazides
Oral administration
Diuresis within one hour
Secreted by organic acid secretory
system, competes with uric acid

Thiazides: Clinical Uses

Essential hypertension
Congestive Heart Failure
Diabetes insipidus
Hypercalciuria

Thiazide Use in Hypercalciuria Recurrent Ca2+ Calculi

promote distal
tubular Ca2+
reabsorption
prevent excess
excretion which
could form stones in
the ducts of the
kidney

Thiazides: 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

Hyponatremia

Potassium-sparing Diuretics

Spironolactone
Synthetic steroid
Mechanism of action:
aldosterone
antagonist
Spironolactone
prevents conversion
of the receptor to
active form, thereby
preventing the action
of aldosterone

Spironolactone: Pharmacokinetics
70% absorption in GI tract
Extensive first pass effect in liver and
enterohepatic circulation
Extensively bound to plasma proteins
100% metabolites in urine

Spironolactone: Clinical Uses

Mineralocorticoid excess
Prevent K loss caused by other diuretics
in:
Hypertension
Refractory edema
Heart failure
Primary aldosteronism

Spironolactone: Toxicity
Hyperkalemia
May range from mild to life-threatening
Androgen like effects due to steroid
structure
Gynecomastia
GI disturbances

Osmotic Diuretic
Prototype: Mannitol
Others: urea, glycerin
Freely filterable
Little or no tubular reabsorption
Inert or non-reactive
Resistant to degradation by tubules

Osmotic Diuretics: MOA

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: Clinical 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

Osmotic Diuretics: Clinical Uses

Reduction of pressure in extravascular fluid
compartments
Reduction of CSF pressure and volume
Reduction of intraocular pressure

Osmotic Diuretics: Toxicity

Increased extracellular fluid volume
Hypersensitivity reactions
Hyperglycemia and glycosuria
Headache, nausea and vomiting

Summary: Sites of Diuretic Action