Management Of Edema Diuretics

Front 1

Pharmacologic modulation of extracellular fluid volume

Back 1

1. To increase or decrease body fluid volume, the kidneys must increase or
decrease renal Na+ reabsorption from the volume of glomerular filtrate.
2. This is accomplished by integrated action of apical and basolateral ion
channels and transporters.
3. Pharmacologic modulators of extracellular fluid volume include agents that
modify neurohormonal volume regulators (e.g., ACEIs and ARBs) and those
that act directly on the nephron segments to alter renal Na+ handling. The
latter category, the diuretics, will be the focus of this presentation.
4. The diuretics directly target renal ion transporter or channel function or
expression to increase renal Na+ excretion and thereby decrease
extracellular fluid volume.

Front 2

Proximal tubule

Back 2

About 67% of sodium reabsorption occurs here
b. Solute absorption is iso-osmotic—water accompanies reabsorbed ions
to maintain ionic balance
c. The proximal tubule is the principle site of action for the carbonic
anhydrase inhibitors (CAIs) (Acetazolamide and dorzolamide) and the
osmotic diuretics (mannitol).

Front 3

Loop of Henle

Back 3

a. The tubular fluid emerging from the thin ascending limb is hypertonic
and has an elevated NaCl concentration.
b. The thick ascending limb (TAL) reabsorbs NaCl without accompanying
water, diluting the tubular fluid.
c. The TAL reabsorbs between 25% and 35% of the filtered Na+ load.
d. The TAL of the loop of Henry is the principle site of action for the loop
diuretics (ethacrynic acid and furosemide).

Front 4

Distal convoluted tubule

Back 4

a. This continuation of the diluting segment reabsorbs between 2% and
10% of the filtered Na+ load, while remaining impermeable to water.
b. The distal tubule is the principle site of action for the thiazide diuretics
(hydrochlorothiazide and indapamide).

Front 5

Collecting duct

Back 5

a. The principal cells of the proximal portions of the collecting duct
reabsorb between 1% and 5% of the filtered Na+ load.
b. The reabsorption of Na+ is dependent upon plasma aldosterone levels
(aldosterone increases Na+ reabsorption and water retention).
c. The collecting duct is the principle site of action for the potassiumsparing
diuretics (Amiloride, spironolactone, and triamterene).

Front 6

Loop diuretics

Back 6

are the most potent

i. The thick ascending limb of the loop of Henle determines the final
magnitude of natriuresis.
ii. Loop diuretics which inhibit reabsorption in the TAL induce a very
large Na+ and water loss. The distal tubule and collecting duct for
Na+ reabsorption are not able to recapture the increased Na+
reaching these sites due to their relatively limited capacity for sodium
reabsorption.
iii. The loop diuretics retain their function in patient’s with very low
creatinine clearance.

Front 7

Thiazide diuretics

Back 7

The modest diuresis caused by the thiazides is due to the fact that 90%
of sodium reabsorption occurs before reaching the distal tubule.

Front 8

Osmotic diuretics

Back 8

Not shown in the table, the osmotic diuretics are about equally effective
with the thiazide diuretics.

Front 9

Carbonic anhydrase inhibitors

Back 9

These drugs which act proximal to the TAL have their natriuretic
response reduced by the ability of the TAL to augment its rate of Na+
reabsorption in the presence of increased tubular Na+ load (see below).

Front 10

Potassium-sparing diuretics

Back 10

i. The collecting duct has a limited capacity to reabsorb solutes, thus
blockade of sodium channels by amiloride and triamterene only
mildly increases the excretion rate of Na+.
ii. Unlike the sodium channel inhibitors, the effects of spironolactone
are a function of the endogenous levels of aldosterone. The higher
the levels of aldosterone, the greater the effects of spironolactone

Front 11

Carbonic anhydrase inhibitors (Acetazolamide and dorzolamide)
1. Mechanism of action

Back 11

a. Na+ reabsorption in the proximal convoluted tubule
i. H+ is extruded into the tubular lumen by Na+/H+ antiporter and
vacuolar ATPase.
ii. The extruded H+ is coupled to HCO3
- reabsorption by apical
membrane carbonic anhydrase (CAIV) which catalyzes cleavage of
HCO3
- into OH- and CO2. The OH- combines with H+ to form water
and the CO2 diffuses into the cell.
iii. The cytoplasmic carbonic anhydrase (CAII) catalyzes formation of
HCO3
- from CO2 and OH-. The bicarbonate is then transported to the
interstitium together with sodium by a basolateral cotransporter

Front 12

Effects of carbonic anhydrase inhibitors

Back 12

i. CAIs inhibit Na+ reabsorption by noncompetitively and reversibly
inhibiting proximal tubule cytoplasmic carbonic anhydrase II and
luminal carbonic anhydrase IV.
ii. This leads to an increase delivery of sodium and biocarbonate to
more distal segments of the nephron.
iii. Much of the sodium bicarbonate is initially excreted causing an
acute decrease in plasma volume (diuresis). Over the course of
several days, however, the diuretic effect is diminished by
compensatory mechanisms resulting in up-regulation of sodium
bicarbonate reaborption and by NaCl reabsorption across more
distal nephron segments.

Front 13

Carbonic anhydrase inhibitors

Administration and elimination

Back 13

a. Acetazolamide administered orally and IV; dorzolamide as eye drops
b. Excreted largely unchanged in the urine—avoid use in severe renal
impairment (drug is ineffective

Front 14

Carbonic anhydrase inhibitors

Adverse effects

Back 14

a. Metabolic acidosis
i. Inhibition of H+ secretion
ii. Inhibition of CA acid secreting-intercalated cells of the collecting
duct
b. These drugs are sulfonamide derivatives thus they may cause allergic
reactions in patients hypersensitive to sulfonamides

Front 15

Carbonic anhydrase inhibitors

Drug interactions

Back 15

Increased urinary pH increases excretion of organic acid anions and
decreases excretion of weak organic bases

Front 16

Carbonic anhydrase inhibitors


Contraindications

Back 16

COPD (increased risk of metabolic acidosis)

Front 17

Carbonic anhydrase inhibitors

Clinical uses

Back 17

a. Dorzolamide reduces formation of aqueous humor and thus lowers
intraocular pressure in treating open angle glaucoma
b. Acetazolamide
i. Acute mountain sickness
ii. Restore acid-base balance in heart failure patients with metabolic
alkalosis caused by loop diuretics

Front 18

Osmotic diuretics (Mannitol)
1. Mechanism of action

Back 18

a. Osmotic diuretics such as mannitol are small molecules that are filtered
at the glomerulus but not subsequently reabsorbed in the nephron.
b. They constitute an intraluminal osmotic force limiting reabsorption of
water across water-permeable nephron segments.
c. This effect is most pronounced in the loop of Henle and the proximal
tubule where most iso-osmotic water reabsorption takes place

Front 19

Osmotic diuretics (Mannitol)

Administration and elimination

Back 19

a. Administered IV
b. Eliminated unchanged in the urine

Front 20

Osmotic diuretics (Mannitol)

Adverse effects

Back 20

Effects on Na+
i. Hypernatremia and dehydration due to water loss in excess of
sodium excretion
ii. Mannitol increases plasma osmolality leading to hyponatremia
(manifested as headache, nausea and vomiting) due to the
movement of fluid into the extracellular compartments

Front 21

Osmotic diuretics (Mannitol)

Contraindications

Back 21

a. Pulmonary congestion (INCR extracellular volume can cause pulmonary
edema)
b. Heart failure (INCR extracellular volume can cause pulmonary edema)
c. Severe renal disease (reduced GFR cannot dissipate the initial increase
in extracellular volume expansion

Front 22

Osmotic diuretics (Mannitol)

Clinical uses

Back 22

Reduce intracranial pressure in neurological conditions
i. The decrease in systemic vascular volume induced by mannitol
causes a reduction in cerebral intravascular volume
ii. In addition, the increase in plasma osmolality contributes to the
movement of fluid from the brain

Front 23

Loop diuretics (Ethacrynic acid and furosemide)
1. Mechanism of action

Back 23

a. Na+ reabsorption in the thick ascending limb of the loop of Henle
i. Na+ is reabsorbed through an apical Na+/K+/2Cl- cotransporter.
ii. The Na+/K+ ATPase pumps sodium into the interstitium.
iii. Basolateral Cl- channel tranports Cl- into the interstitium
iv. K+ is recycled into the urinary space by a luminal K+ channel.
v. The combined activities of the K+ and Cl- channels is a lumenpositive
transepithelial potential difference (about 10 mV) which
drives paracellular absorption of cations

Front 24

Effects of loop diuretics

Back 24

i. These drugs reversibly and competitively inhibit the Na+/K+/2Clcotransporter
thus inhibiting Na+ reabsorption.
ii. This abolishes the transepithelial potential resulting in increased
excretion of cations, particularly Mg++ and Ca++.
iii. The increase in tubular flow increases K+ secretion by washing the
K+ downstream thus minimizing the rise in tubular [K+]. The rise in
tubular flow also increases the amount of sodium entering the distal
tubule and collecting duct, which in turn enhances Na+ reabsorption
and the lumen negative potential favoring K+ secretion. Finally, the
increase in Na+ reabsorption stimulates K+ uptake across the
basolateral membrane by increasing the activity of the Na+/K+
ATPase which promotes K+ secretion.
iv. Inasmuch as 20% of the filtered Na+ load is reabsorbed by the loop
of Henle, these drugs are the most effective diuretics

Front 25

Loop diuretics (Ethacrynic acid and furosemide)

Administration and elimination

Back 25

a. Administered orally and IV
b. The drugs are actively secreted into the tubular lumen
c. Eliminated in the feces and urine as unchanged drug—in cases of
severe renal impairment large doses (grams) may be necessary to
initiate diuresis

Front 26

Loop diuretics (Ethacrynic acid and furosemide)

Adverse effects

Back 26

a. Effects on electrolytes
i. Hypocalcemia
ii. Hypomagnesemia
iii. Hypokalemia (predisposes patient to cardiac arrythmias)
iv. Metabolic alkalosis
b. Ototoxicity manifested as hearing impairment, tinnitus, deafness, and
vertigo (reversible with furosemide; irreversible with ethacrynic
acid)—occurs with rapid IV infusion (maintain infusion rate < 4 mg/min)
c. Furosemide is a sulfonamide derivative and thus it may cause allergic
reactions in patients hypersensitive to sulfonamides (Ethacrynic acid is
NOT)
d. Decreased glucose tolerance (may be due to impairment of insulin
secretion or decreased peripheral insulin sensitivity; insulin secretion is
increased by potassium, thus hypokalemia caused by loop diuretics may
contribute to the decrease in insulin secretion)

Front 27

Loop diuretics (Ethacrynic acid and furosemide)

Drug interactions

Back 27

a. Aminoglycosides (synergism of ototoxicity)
b. NSAIDs can decrease effectiveness of loop diuretics (loop diuretics
increase prostaglandin production which contribute to vascular effects of
loop diuretics [vasodilation])
c. Oral hypoglycemics (Loop diuretics decrease glucose tolerance, may
need to increase dose of oral hypoglycemic agents)

Front 28

Loop diuretics (Ethacrynic acid and furosemide)

Contraindications

Back 28

a. Patients with hypersensitivity to sulfonamide derivatives (Ethacrynic acid
would be an alternative)

Front 29

Loop diuretics (Ethacrynic acid and furosemide)

Clinical uses

Back 29

a. Relief of pulmonary and peripheral edema
b. Relief of edema associated with hypoalbuminemia (caused by liver
disease or nephrotic proteinuria)
c. Increased calcium diuresis is used to provide relief for hypercalcemia
caused by hyperparathyroidism or malignancy-associated
hypercalcemia; saline is administered concurrently to prevent volume
depletion.
d. Counteract hyperkalemia caused by potassium-retaining drugs or renal
insufficiency with impaired K+ excretion
e. Treatment of hyponatremia; Loop diuretics interfere with the kidney’s
ability to produce a concentrated urine. Loop diuretics (to cause diuresis)
in combination with hypertonic saline (to replace sodium) are useful for
the treatment of life-threatening hyponatremia.

Front 30

Thiazide diuretics (Hydrochlorothiazide and indapamide)
1. Mechanism of action

Back 30

a. Na+ reabsorption in the distal convoluted tubule
i. Na+ enters the epithelial cells via the Na+/Cl- cotransporter.
ii. Basolateral exit of sodium is mediated by Na+/K+ ATPase
iii. Basolateral exit of Cl- occurs via Cl- channels.
iv. Ca++ and Mg++ reabsorption occurs through channels in the apical
membrane (only Ca++ channel shown). The ions cross the
basolateral membrane via specific exchangers (only Ca++/Na+
exchanger shown) and by ATPases.

Front 31

Effects of thiazide diuretics

Back 31

i. These drugs are competitive antagonists of the Na+/Clcotransporter.
ii. Thiazides promote transcellular reabsorption of calcium (may be due
to increased expression of Ca++ channels and the Ca++/Na+
exchanger)

Front 32

Thiazide diuretics (Hydrochlorothiazide and indapamide)

Administration and elimination

Back 32

a. Orally administered
b. The drugs are actively secreted into the tubular lumen
c. Hydrochlorothiazide excreted in urine—avoid use in severe renal
impairment; indapamide is extensively metabolized by the liver

Front 33

Thiazide diuretics (Hydrochlorothiazide and indapamide)

Adverse effects

Back 33

a. Hypokalemia (due to increased delivery of Na+ to the collecting duct)
b. Impaired glucose tolerance (may be due to impairment of insulin
secretion or decreased peripheral insulin sensitivity; insulin secretion is
increased by potassium, thus hypokalemia caused by thiazide diuretics
may contribute to the decrease in insulin secretion)
c. Hyperuricemia (The thiazides compete with uric acid for active secretory
sites in the proximal tubule thus inhibiting active secretion of uric acid;
patients with gout may be particularly susceptible to the increase levels
of uric acid)
d. Thiazides are sulfonamide derivatives and thus they may cause allergic
reactions in patients hypersensitive to sulfonamides

Front 34

Thiazide diuretics (Hydrochlorothiazide and indapamide)

Drug interactions

Back 34

a. Oral hypoglycemics (decreased effect of oral hyoglycemics)
b. NSAIDs (decrease the efficacy of thiazides)
c. Loop diuretics (synergistic effect when combined with a thiazide diuretic)

Front 35

Thiazide diuretics (Hydrochlorothiazide and indapamide)

Contraindications

Back 35

a. Patients with hypersensitivity to sulfonamide derivatives (Ethacrynic acid
would be an alternative)
b. Anuria

Front 36

Thiazide diuretics (Hydrochlorothiazide and indapamide)

Clinical uses

Back 36

a. Diminish hypercalciuria in patients at risk for nephrolithiasis
b. Hypertension (first-line drugs)
c. Thiazide and loop diuretics used in combination in heart failure
d. Nephrogenic diabetes insipidus (These kidneys of these patients do not
respond to ADH and thiazides can produce a modest decrease in urine
flow. This seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular
reabsorption of Na+ and water. Therefore a reduced volume is delivered
to the distal tubule.)

Front 37

Potassium-Sparing Diuretics (Amiloride, spironolactone, triamterene)
1. Mechanism of action

Back 37

a. Na+ reabsorption in the collecting duct
i. Luminal Na+ enters the principal cell via a Na+ channel.
ii. The Na+ exits the basolateral membrane via a Na+/K+ ATPase
iii. The collecting duct cells express apical K+ channels that allow K+ to
exit into the lumen
iv. Expression of Na+ channels and Na+/K+ ATPase is modulated by
aldosterone.

Front 38

Actions of potassium-sparing diuretics

Back 38

i. Spironolactone inhibits synthesis of new Na+ channels (and new
Na+/K+ ATPase) in the principal cells by binding to and preventing
nuclear translocation of the mineralcorticoid (aldosterone) receptor.
ii. Amiloride and triamterene are competitive inhibitors of the apical
membrane Na+ channel.
iii. These drugs decrease K+ excretion by decreasing the lumen negative
potential and thus decreasing the driving force for K+.
iv. Proton secretion also is diminished by the decrease in Na+ uptake.

Front 39

Potassium-Sparing Diuretics (Amiloride, spironolactone, triamterene)

Administration and elimination

Back 39

a. Administered orally
b. Metabolized in the liver and excreted in the urine and feces. Avoid use in
severe renal impairment

Front 40

Potassium-Sparing Diuretics (Amiloride, spironolactone, triamterene)

Adverse effects

Back 40

a. Hyperkalemia
b. Metabolic acidosis
c. Impotence and gynecomastia caused by the antiandrogenic effects of
spironolactone (not with amiloride or triamterene)

Front 41

Potassium-Sparing Diuretics (Amiloride, spironolactone, triamterene)

Drug interactions

Back 41

a. Concurrent use of these drugs with other potassium-sparing diuretics,
potassium supplements, ARBs, or ACEIs can increase the risk of
hyperkalemia
b. NSAIDs can decrease effectiveness

Front 42

Potassium-Sparing Diuretics (Amiloride, spironolactone, triamterene)

Contraindications

Back 42

a. Anuria
b. Hyperkalemia
c. Concurrent use of potassium-sparing drugs, potassium supplements,
ARBs, or ACEIs

Front 43

Potassium-Sparing Diuretics (Amiloride, spironolactone, triamterene)

Clinical uses

Back 43

a. Potentiate the action of more proximally acting diuretics
b. Counteract the potassium wasting of thiazide and loop diuretics
c. Sprionolactone
i. Heart failure (decrease mortality)
ii. Treatment of ascites and edema associated with impaired plasma
protein biosynthesis secondary to hepatic failure
iii. Hypokalemic alkalosis secondary to mineralcorticoid excess that
accompany heart failure, hepatic failure, and other diseases
associated with diminished aldosterone metabolism
d. Amiloride is used in treating lithium-induced nephrogenic diabetes
insipidus (Lithium may inhibit the action of vasopressin on renal adenyly
cyclase causing a lack of responsiveness to vasopressin and polyuria.
Amiloride blocks the uptake of lithium by the Na+ channel in the
collecting duct

Front 44

1. Heart failure

Back 44

Front 45

Cirrhosis

Back 45

Cirrhosis is caused by hepatic parenchymal fibrosis resulting from chronic
inflammation or hepatotoxic insult. The fibrotic changes obstruct venous
outflow from the liver and increase hydrostatic pressure in the portal vein.
Hepatocellular injury disrupts the synthetic and metabolic functions of the
liver leading to decreased production of albumin and other contributors to
plasma oncotic pressure. Serous fluid accumulates in the abdominal cavity
(ascites) which decreases intravascular volume leading to decreased
cardiac output leading to increased Na+ retention by a mechanism similar to
that described above for heart failure.
Diuretics include Spironolactone, loop diuretics and thiazides

Front 46

Nephrotic syndrome

Back 46

Nephrotic syndrome is characterized by massive proteinuria, edema, and
hypoalbuminemia. The primary cause is glomerular dysfunction. The
proteinuria leads to decreased plasma oncotic pressure leading to fluid
transudation into the interstitium. This transudation decreases intravascular
volume ultimately enhancing renal Na+ retention.
Diuretics include Spironolactone, loop diuretics and thiazides

Front 47

Carbonic anhydrase inhibitors

Back 47

a. Acute mountain sickness - acetazolamide
b. Glaucoma - dorzolamide
c. Restore acid-base balance in heart failure patients with metabolic
alkalosis caused by loop diuretics - acetazolamide

Front 48

Osmotic diuretics

Back 48

Reduce intracranial pressure in neurological conditions

Front 49

Loop diuretics

Back 49

a. Hypercalcemia
b. Hyponatremia (administered with hypertonic saline)
c. Counteract hyperkalemia caused by potassium-retaining drugs or renal
insufficiency with impaired K+ excretion

Front 50

Thiazides

Back 50

a. Hypertension
b. Nephrolithiasis
c. Nephrogenic diabetes insipidus
d. Counteract hyperkalemia caused by potassium-retaining drugs or renal
insufficiency with impaired K+ excretion

Front 51

Potassium sparing diuretics

Back 51

a. Lithium-induced nephrogenic diabetes insipidus - amiloride
b. Counteract the potassium wasting of thiazide and loop diuretics