High-Ceiling, or Loop, Diuretics
The compounds known as high-ceiling or loop diuretics are the most efficacious agents available for
inducing marked water and electrolyte excretion. They can in-crease diuresis
even in patients who are already re-sponding maximally to other diuretics. The
drugs in this group available for use in the United States include furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex),
and ethacrynic acid (Edecrin).
Although these agents differ somewhat, they share a common pri-mary site of
action, which underlies their effectiveness.
The site of action of loop diuretics is the thick ascending limb of
the loop of Henle, and diuresis is brought about by inhibition of the NA+
–K+ –2Cl- transporter. This seg- ment of the nephron is critical for
determining the final magnitude of natriuresis.As much as 20% of the filtered NA+
may be reabsorbed by the loop of Henle. The im-portance of the loop is further
emphasized by the real-ization that drugs that primarily inhibit proximal NA+
and fluid reabsorption have their natriuretic response reduced by the ability
of the ascending limb to augment its rate of NA+ reabsorption in the
presence of an in-creased tubular NA+ load. Thus, any agent that greatly impairs active reabsorption in the thick
ascending limb may induce a very large NA+ and water loss. Further-more,
the relatively limited capacity of the distal tubule and collecting duct for NA+
reabsorption makes it im-possible to recapture much of the suddenly increased
tubular NA+ reaching them.
Since the thick ascending
limb is responsible for ini-tiating events that lead to the hyperosmolar
medullary interstitium (and therefore providing the driving force for water
reabsorption from the collecting ducts under the influence of ADH), it is this
nephron segment that underlies urinary concentration. Thus, drugs that
inter-fere with this concentrating function will have marked effects on urinary
output.
During the peak effect of the
loop diuretics, urine flow is greatly augmented, as is the excretion of NA+
and Cl- , corresponding to as much as 20 to 30% of their filtered
load. K+ loss also occurs as an indirect effect of the large NA+
load reaching the distal tubules and is 2 to 5 times above normal levels of K+
excretion. With low or mod-erately effective doses, these drugs do not
appreciably affect HCO3- or H+ excretion.
Furosemide (Lasix), torsemide (Demadex), and bumetanide (Bumex)
possess some carbonic anhydrase inhibiting activity (about one-tenth that of
chloroth-iazide). This property may account for the increased bi-carbonate and
phosphate excretion seen after large doses of these diuretics. The elevated HCO3-
loss prob-ably indicates some proximal tubular effects for furosemide and
bumetanide.
All of the loop diuretics are
available for both oral and parenteral administration. Their onset of action is
rapid, usually within 30 minutes after oral and 5 minutes after intravenous
administration. They produce peak diuresis in about 2 hours, with a total
duration of diuretic action of approximately 6 to 8 hours. Loop diuretics are
exten-sively bound to plasma proteins and are eliminated in the urine by both
glomerular filtration and tubular se-cretion. Approximately a third of an
administered dose is excreted by the liver into the bile, from where it may be
eliminated in the feces. Only small amounts of these compounds appear to be metabolized
by the liver.
The loop diuretics must be
present in the tubular fluid before they can become effective. Because of their
extensive binding to plasma proteins, filtration across the glomerular
capillaries is restricted. Like the thi-azides, however, the loop diuretics are
weak organic acids that are substrates for the organic acid secretory system in
the proximal tubule.A consequence of this ac-tive secretion is that the
presence of other organic acids or certain forms of renal disease may impair the
thera-peutic usefulness of the loop diuretics.
Because diuresis may be
extensive, loop diuretics should be administered initially in small doses;
multiple doses, if needed, should be given in early morning and early
afternoon. During the remainder of the day, when the drug is not acting, the
body can begin to compensate for any derangements in fluid and electrolyte
balance that may have occurred as a result of drug therapy. These drugs should
be restricted to patients who re-quire greater diuretic potential than can be
achieved by other diuretic drugs. In addition to being used in the usual
edematous states associated with congestive heart failure, cirrhosis, or renal
disease, the loop diuretics can be used in emergencies, such as acute pulmonary
edema, when rapid onset of action is essential. They are not recommended for
use during pregnancy.
Frequent serum electrolyte analysis is essential during therapy
with the high-ceiling diuretics. Overdose may re-sult in a rapid reduction of
blood volume, dizziness, headache, orthostatic hypotension, hyponatremia, and
hypokalemia. Nausea, vomiting, diarrhea, and loss of appetite are especially
common with ethacrynic acid.
Ototoxicity has been reported during therapy with all loop diuretics.
This
effect seems to be dose related and is
most common in patients with renal insufficiency. Deafness is usually reversed
when these drugs are dis-continued, but irreversible hearing loss has been
re-ported after administration of ethacrynic acid, and this has led to a marked
decrease in its use.
Furosemide, torsemide, and
bumetanide are sulfon-amide derivatives, hence chemically related to the
thi-azides. They share the thiazides’ adverse effects of serum uric acid
elevation and diabetogenic potential. Ethacrynic acid (Edecrin) is chemically unrelated to other diuretics and does not
appear to have diabeto-genic potential.
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