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.