Diuretics
A
diuretic is anything that increases urine
production. Using this definition, water is considered a diuretic, as the
intake of an increased volume of water will increase urine production. A
clinically effective diuretic will enhance the urinary excretion of
sodium as well as water. Therefore water is a diuretic but not a clinically
effective one.
Indications for the use of a diuretic
include
- treatment of edema which may be caused by congestive heart failure
or hypoalbuminemia
- treatment of iatrogenic fluid overload
- treatment of oliguric acute renal failure patients in attempt to
induce diuresis BUT ONLY ONCE THE PATIENT IS REHYDRATED.
Diuretics are most often misused in renal disease. Diuretics should NEVER
be administered to dehydrated patients.
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The
potency of a diuretic is determined by its
ability to result in sodium loss in the urine. This ability is measured as
fractional sodium excretion. Fractional sodium excretion is the percentage
of filtered sodium which is excreted in the urine. The more potent the
diuretic, the greater the ability to interfere with the reabsorption of
sodium from the renal tubules resulting in a larger amount of sodium
remaining in the excreted urine. The greater the amount of sodium in the
urine, the greater the volume of urine.
Potent diuretics include
- Furosemide (25% fractional sodium excretion)
- Ethacrynic acid (25% fractional sodium excretion)
Moderately potent diuretics include the thiazides (10% fractional sodium
excretion)
Weak diuretics include
- osmotic diuretics
- carbonic anhydrase inhibitors (5% fractional sodium excretion)
- aldosterone antagonists (2% fractional sodium excretion)
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Diuretics are classified by their
mechanism of action. Diuretics work at different locations
within the nephron.
The
classes of diuretics include:
- osmotics
- inhibitors of urinary acidification
- thiazides
- loop diuretics
- aldosterone antagonists
- xanthines
Osmotic diuretics
include any low molecular weight substance that is freely filtered by the
glomeruli but poorly reabsorbed from tubular fluid. Examples include:
- urea which is increased in blood in azotemic states acts as an
endogenous diuretic
- glucose which is increased in diabetes mellitus or by exogenous
administration
- mannitol which is most commonly used to reduce neuronal edema in
patients with CNS signs and less commonly is used in the oliguric ARF
patient.
Osmotic diuretics cause expansion of the extracellular fluid volume by
relocating intracellular fluid to the extracellular space, specifically to
the plasma.
 |
Distribution of body fluids
Extracellular fluid includes both plasma (fluid in blood
vessels) and interstitial fluids. |
Each 50 ml of a 25% mannitol solution draws 225 ml of fluid from cells
into the blood vessels. The expanded blood volume leads to increased renal
blood flow which results in a larger amount of blood being filtered into
glomerular filtrate. Osmotic diuretics also prevent reabsorption of sodium
and water from the renal tubules which results in a larger volume of urine
being produced. Mannitol doesn't cross the blood-brain-barrier readily.
Therefore mannitol will draw water out of neuronal cells and is used to
treat brain edema.
| Mini quiz: |
You plan to deliver a dose of 1g/kg IV of mannitol to a 50
kg dog. What volume of a 25% solution will you administer? How
much fluid might this mobilize from the intracellular
compartment to the vascular space? By what percent will this
increase the dog's blood volume?
ANSWER |
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Inhibitors of urinary
acidification:
Carbon dioxide is produced in renal tubular epithelial cells or is
brought to the kidneys in the blood. (1) Carbon
dioxide reacts with water in the presence of carbonic anhydrase (CA) to form
carbonic acid.(2) Carbonic acid spontaneously breaks
down to hydrogen ion and bicarbonate.(3) This
bicarbonate is reabsorbed.
(3) Water in the cell ionizes to hydrogen and hydroxyl
ions. Hydrogen ions from the above 2 sources exchange for sodium in the
tubular fluid. The secreted hydrogen ion (4) combines
with bicarbonate
(5) in the tubular fluid to form carbonic acid
(6) that disassociates into water and carbon dioxide
(7). The carbon dioxide equilibrates across the renal
tubular epithelium. The end result is that for each bicarbonate filtered
into tubular fluid one bicarbonate is reabsorbed. The blue numbers on the
diagram correlate with the blue numbers in the text above.
Diuretics which inhibit the enzyme carbonic anhydrase impair the
reabsorption of bicarbonate from tubular fluid. Sodium and water are
eliminated in urine in conjunction with the lost bicarbonate.
Acetazolamide is an example of this class of diuretics. The bicarbonate
in the tubular fluid is negatively charged and will draw positively charged
ions such as potassium into the urine, enhancing the loss of potassium. Some
of the sodium which normally would have been reabsorbed from tubular fluid
paired with bicarbonate will be reabsorbed with chloride instead. (for each
negatively charged ion reabsorbed, one positively charged ion will be
reabsorbed as well.) The increased reabsorption of chloride and increased
loss of potassium coupled with impaired ability to reabsorb bicarbonate can
lead to hyperchloremic acidosis and hypokalemia.
 |
Carbonic anhydrase is also found in the eye where it is involved
in the production of aqueous humour. Carbonic anhydrase
inhibiting diuretics are most often used to reduce the
production aqueous humour in patients with glaucoma. The
diuretic effects occur in conjunction with the effects on fluid
production in the eye. Therefore the side effects of acidosis,
hyperchloridemia, hypokalemia and dehydration may occur in
treated patients. |
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Thiazides
such as hydrochlorothiazide are moderately potent diuretics. They inhibit
carbonic anhydrase to a minor degree and more importantly, impede the
reabsorption of sodium and chloride in the distal convoluted tubule and loop
of Henle. The end result is increased excretion of Na, Cl, K and water.
Additionally thiazide diuretics decrease renal excretion of calcium and
therefore should not be given to hypercalcemic patients. Potential side
effects of thiazides include hypokalemia and metabolic alkalosis. Alkalosis
occurs as the sodium which is reabsorbed is absorbed primarily with
bicarbonate as the reabsorption of chloride is blocked. Thiazides are used
in the treatment of arterial hypertension and may have some direct relaxing
effect on vascular smooth muscle in addition to the diuretic effect.
Thiaizide diuretics may decrease the severity of polyuria in patients with
diabetes insipidus (decrease urine volume by 30-40%). It is not clear how a
diuretic actually decreases
urine volume in these patients.
 |
Loop
diuretics include furosemide (lasix; most commonly used
diuretic in dogs and cats) and ethacrynic acid. They have a
rapid oral, IV, and IM absoprtion. There is a diuretic effect
within minutes which persists for 1-3 hours. The action is to
strongly inhibit Cl pump in ascending loop of Henle (and
subsequently Na reabsorption). They can produce hypokalemia and
metabolic alkalosis. |
Aldosterone antagonists like
spironolactone compete with aldosterone for its physiologic binding site
with ~1/1000 the affinity for the binding site. Aldosterone antagonists
are usually given with other, more potent, diuretics for their effect of
potassium sparing. Hyperkalemia is a possible side effect.
 |
Xanthines
include caffeine, theobromine, and theophylline which is a
bronchodilator. Xanthines act to increase cardiac output which
increases RBF and GFR resulting in a modest loss of Na, Cl, and
water. Additionally a direct tubular action is suspected as
their effect persists after RBF and GFR return to normal. |
Drugs which inhibit the secretion or action of ADH causing a state of
nephrogenic diabetes insipidus, include water, narcotics, anesthetics,
alcohol, and corticosteroids.
The most common
side effects of diuretics include fluid depletion
which may result in hypotension and prerenal azotemia and potassium
depletion which may result in skeletal and smooth muscle weakness and
cardiac arrhythmia. Work up a
case of a patient receiving a diuretic.
Last Edited: Apr 28, 2008 5:03 PM
