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.
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Revised July 26, 2007
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