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DIURETICS
I.
Kidney Functions
A.
Normal Conditions
1.
Maintain internal environment by regulating composition of
extracellular compartment.
a)
Volume
b)
Acid-base balance
c)
Osmotic pressure
d)
Electrolyte concentration
e)
Excretion of metabolites and toxic substances
B.
Pathological conditions
1.
Excessive retention of sodium and water
a)
Development of edema
b)
Development of ascites
c)
Hypertension, cirrhosis, heart failure, renal failure (acute/chronic)
C.
Structure of kidney
1.
Nephron
Glomerulus
Proximal convoluted tubule
Loop of Henle
(1)
Thin descending segment
(2)
Thin ascending segment
(3)
Thick ascending segment
(4)
Distal convoluted tubule
(5)
Collecting duct
Basic processes of renal function
1.
Glomerular filtration
2.
Tubular Secretion
a)
Organic acid secretory pathway
b)
Organic base secretory pathway
a)
b)
c)
B.
Table 1: Average Values for Several Substances
Handled by Filtration and Reabsorption
Substance
Water, L
Sodium, g
Glucose, g
Urea, g
C.
II.
Amount
Filtered
per Day
180
630
180
56
Amount
%
Excreted Reabsorbed
1.8
99.0
3.2
99.5
0
100
28
50
Table 2: Some Organic Anions Actively
Secreted by the Proximal Tubule
Endogenous Substances
Bile salts
Fatty acids
Hippurates
Hydroxybensoates
Oxalate
Prostaglandins
Urate
Drugs
Acetazolamide
Chlorothiazide
Ethacrynate
Furosemide
Probenecid
Saccharin
Salicylates
Sulfonamides
Importance of sodium ion
1.
With anion, responsible for 90% of extracellular osmotic pressure
2.
Volume of extracellular compartment dependent primarily on quantity
of sodium
D.
Goal of diuretic therapy
1.
To promote the excretion of sodium and subsequently water by the
kidneys
Proximal convoluted tubule
A.
Sodium reabsorption (range 50-90%)
1.
Na-K-ATPase mechanism
2.
Bicarbonate - carbonic anhydrase mechanism
B.
Water reabsorption (range 50-90%)
1.
Passive, freely permeable
2.
dependent on solute reabsorption
C.
Proximal tubule diuretics
1.
Osmotic diuretics
a)
Drugs
(1)
Mannitol
(2)
Urea
(3)
Glycerin
(4)
Isosorbide
b)
Mechanism of action
(1)
After filtration, osmotic diuretics remain in the lumen
and create an osmotic force that inhibits passive
reabsorption of water, thus increasing urine output.
c)
Urine excretion pattern
(1)
Increases in: H20, Na+, Cl-, HCO3, pH
(2)
Decreases in: H+, NH4+
d)
Therapeutic Uses
(1)
Maintain urine flow
(2)
Reduce cerebrospinal fluid volume and pressure
(3)
Glaucoma
(4)
Facilitate urinary excretion of toxic substances
e)
Adverse effects
(1)
Extracellular expansion and subsequent adverse
effects in patients with congestive heart failure and
pulmonary edema
2.
Carbonic anhydrase inhibitors
a)
Drugs
b)
c)
d)
e)
III.
(1)
Acetazolamide
Mechanism of action
(1)
Inhibition of carbonic anhydrase enzyme
Urine excretion pattern
(1)
Increases in: H20, Na+, HCO3-, K+, pH
(2)
Decreases in: Cl-, H+, NH4+
Therapeutic Uses
(1)
Glaucoma
(2)
Excretion of acidic drugs
(3)
Treatment of metabolic alkalosis
Adverse effects
(1)
Metabolic acidosis
Loop of Henle
A.
Descending limb of Loop of Henle (concentrating segment)
1.
Passive reabsorption of water (10-15%)
2.
Impermeable to electrolytes
B.
Ascending limb of Loop of Henle
1.
Thin segment
a)
Water impermeable
b)
Some passive reabsorption of Na+ and Cl2.
Thick segment
a)
Water impermeable
b)
Sodium chloride reabsorption (25-60%)
(1)
Active Na-K-ATPase on basolateral membrane
(2)
Luminal Na-K-2Cl co-transport
C.
Loop diuretics (high ceiling diuretics)
1.
Drugs
a)
Furosemide (Lasix)
b)
Ethacrynic acid (Edecrin)
c)
Bumetanide (Bumex)
d)
Torsemide (Demadex)
2.
Mechanism of action
a)
Inhibition of Na-K-2Cl carrier process on luminal membrane of
cortical and medullary segments of thick ascending limb of
Loop of Henle.
3.
IV.
Urine excretion pattern
a)
Increases in: H20, Na+, Cl-, K+
b)
Also increases in Ca+, H+, NH4+ (thought to be due to effects
on distal nephron)
c)
Decreases in: pH
d)
Relatively no change in HCO34.
Therapeutic Uses
a)
Removal of edema (e.g. acute pulmonary edema, etc.)
b)
Hypertension - caution with use
c)
Symptomatic hypercalcemia
d)
Hyponatremia
5.
Adverse Effects
a)
Volume depletion and circulatory contraction
b)
Diuretic-induced hyponatremia
c)
Diuretic-induced metabolic alkalosis
d)
Hypokalemia
e)
Ototoxicity
f)
Drug interactions
(1)
Anticoagulants (Warfarin)
(2)
Aminoglycosides
(3)
Cardiac glycosides
(4)
Drugs that utilize the proximal tubule organic acid
secretory pathway (e.g. probenecid, penicillin,
salicylates, etc.)
Distal convoluted tubule
A.
Early distal tubule (diluting segment)
1.
2.
B.
Water impermeable
Sodium chloride reabsorption (range 8-10%)
a)
Active Na-K-ATPase on basolateral membrane
b)
Luminal reabsorption of Na+ driven by electrochemical
gradient
Early distal tubule diuretics
1.
Drugs - Benzothiadiazide (Thiazides)
a)
Chlorothiazide (Diuril)
b)
Hydrochlorothiazide (Hydrodiuril)
c)
Chlorothalidone (Hygroton)
d)
Metolazone (Diulo)
2.
Mechanism of action
a)
Inhibition of Na-Cl co-transporter on luminal membrane of
early distal tubule
3.
V.
Urine excretion pattern
a)
Increases in: H20, Na+, Cl-, K+, HCO3-, pH
b)
Decreases in: Ca+, H+, NH4+
4.
Therapeutic Uses
a)
Hypertension
b)
Removal of edema and ascites
c)
Nephrogenic diabetes insipidus
d)
Hypocalcemia
5.
Adverse effects
a)
Volume depletion and circulatory contraction
b)
Hypokalemia
c)
Drug interactions
(1)
Cardiac glycosides
(2)
Drugs that utilize the proximal tubule organic acid
secretory pathway.
Late distal tubule (Cortical collecting tubule)
A.
Sodium Chloride Reabsorption (range 2%)
1.
Aldosterone-dependent
a)
Active Na-K-ATPase on basolateral membrane
b)
In the presence of aldosterone, luminal reabsorption of sodium
is driven by electrochemical gradient
c)
Luminal sodium-potassium exchange
2.
B.
C.
Aldosterone-Independent
a)
Luminal reabsorption of sodium is driven by electrochemical
gradient
Water Reabsorption
1.
Antidiuretic hormone-dependent
Late tubule diuretics (Potassium sparing diuretics
1.
Aldosterone antagonists
a)
Drugs
(1)
Spironolactone (Aldactane)
b)
Mechanism of action
(1)
Competitive antagonist of aldosterone
c)
Urine excretion pattern
(1)
Increases in: H20, Na+, Cl-, HCO3-, pH
(2)
Decreases in: K+, H+, NH4+
d)
Therapeutic Uses
(1)
Hypertension
(2)
Refractory edema and ascites
(3)
Hypokalemia
e)
Adverse effects
(1)
Hyperkalemia
2.
Other potassium sparing diuretics
a)
Drugs
(1)
Triamterene (Midamor)
(2)
Amiloride (Dyrenium)
b)
Mechanism of action
(1)
Direct inhibition of luminal sodium reabsorption in
collecting tubule and collecting duct (aldosteroneindependent)
c)
Urine excretion pattern
(1)
Increases in: H20, Na+, Cl-, HCO3-, pH
(2)
Decreases in: K+, H+, NH4+
d)
Therapeutic Uses
(1)
Hypertension
(2)
Refractory edema and ascites
(3)
Hypokalemia
e)
Adverse effects
(1)
Hyperkalemia
VI.
VII.
VIII.
Distal tubule diuretics
A.
Drugs
1.
Conivaptan
2.
Lithium, Demeclocycline
B.
Mechanism of action
1.
Prevents antidiuretic hormone’s action to increase water permeability
in the collecting duct (i.e. non-competitive ADH antagonist).
C.
Urine excretion pattern
1.
Produces a dilute urine of low osmolality (i.e. evokes a free water
diuresis).
D.
Therapeutic uses
1.
hyponatremia
2.
Inappropriate antidiuretic hormone secretion
E.
Adverse effects
1.
Dehydration and circulatory contraction
Distal tubule antidiuretics
A.
Drugs
1.
Desmopressin (DDAVP)
B.
Mechanism of action
1.
Synthetic analogue of antidiuretic hormone - increases water
permeability of cortical collecting tubules and collecting duct.
C.
Urine excretion pattern
1.
Produces a concentrated urine with increased osmolality
D.
Therapeutic uses
1.
Drug of choice for treatment of central diabetes insipidus
Other drugs with diuretic activity
A.
Drugs
1.
Methylxanthines
2.
Dopamine, dobutamine, cardiac glycosides
3.
Alcohol
4.
Water