Page 277 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 263

the loop diuretics reduce the reabsorption of NaCl and also dimin- C. Anion Overdose
+
ish the lumen-positive potential that comes from K recycling Loop diuretics are useful in treating toxic ingestions of bromide,
(Figure 15–3). This positive potential normally drives divalent fluoride, and iodide, which are reabsorbed in the TAL. Saline solu-
cation reabsorption in the TAL (Figure 15–3), and by reducing tion must be administered to replace urinary losses of Na and to
+
2+
2+
this potential, loop diuretics cause an increase in Mg and Ca provide Cl , so as to avoid extracellular fluid volume depletion.
−
excretion. Prolonged use can cause significant hypomagnesemia
in some patients. Since vitamin D–induced intestinal absorption
2+
and parathyroid hormone–induced renal reabsorption of Ca can Toxicity
be increased, loop diuretics do not generally cause hypocalcemia. A. Hypokalemic Metabolic Alkalosis
2+
However, in disorders that cause hypercalcemia, Ca excretion By inhibiting salt reabsorption in the TAL, loop diuretics increase
can be enhanced by treatment with loop diuretics combined with Na delivery to the collecting duct. Increased Na delivery leads to
+
+
saline infusion. increased secretion of K and H by the duct, causing hypokalemic
+
+
Loop diuretics have also been shown to induce expression of metabolic alkalosis (Table 15–2). This toxicity is very common and
the cyclooxygenase COX-2, which participates in the synthesis is a function of the magnitude of the diuresis and can be reversed by
of prostaglandins from arachidonic acid. At least one of these K replacement and correction of hypovolemia. At least one study
+
prostaglandins, PGE , inhibits salt transport in the TAL and thus has found that potassium supplementation upon initiation of loop
2
participates in the renal actions of loop diuretics. NSAIDs (eg, diuretics, irrespective of the serum potassium concentration, will
indomethacin), which blunt cyclooxygenase activity, can inter- improve survival.
fere with the actions of loop diuretics by reducing prostaglandin
synthesis in the kidney. This interference is minimal in otherwise B. Ototoxicity
normal subjects but may be significant in patients with nephrotic
syndrome or hepatic cirrhosis. Loop diuretics occasionally cause dose-related hearing loss that
Loop agents have direct effects on blood flow through several is usually reversible. It is most common in patients who have
vascular beds. Furosemide increases renal blood flow via pros- diminished renal function or who are also receiving other ototoxic
taglandin actions on kidney vasculature. Both furosemide and agents such as aminoglycoside antibiotics.
ethacrynic acid have also been shown to reduce pulmonary con-
gestion and left ventricular filling pressures in heart failure before C. Hyperuricemia
a measurable increase in urinary output occurs. These effects on Loop diuretics can cause hyperuricemia and precipitate attacks of
peripheral vascular tone are also due to release of renal prostaglan- gout. This is caused by hypovolemia-associated enhancement of
dins that are induced by the diuretics. uric acid reabsorption in the proximal tubule. It may be prevented
by using lower doses to avoid development of hypovolemia.
Clinical Indications & Dosage D. Hypomagnesemia

The most important indications for the use of the loop diuretics Magnesium depletion is a predictable consequence of the chronic
include acute pulmonary edema and other edematous condi- use of loop agents and occurs most often in patients with dietary
tions. Many times the treatment of the fluid overload will also magnesium deficiency. It can be reversed by administration of oral
serve as an effective anti-hypertensive agent, especially in the magnesium preparations.
presence of renal insufficiency. The use of loop diuretics in these
conditions is discussed below in Clinical Pharmacology of Diuretic E. Allergic and Other Reactions
Agents. Other indications for loop diuretics include hypercalce- All loop diuretics, with the exception of ethacrynic acid, are
mia, hyperkalemia, acute renal failure, and anion overdose. sulfonamides. Therefore, skin rash, eosinophilia, and less often,
interstitial nephritis are occasional adverse effects of these drugs.
A. Hyperkalemia This toxicity usually resolves rapidly after drug withdrawal. Allergic
In mild hyperkalemia—or after acute management of severe reactions are much less common with ethacrynic acid.
hyperkalemia by other measures—loop diuretics can significantly Because Henle’s loop is indirectly responsible for water reab-
+
enhance urinary excretion of K . This response is enhanced by sorption by the downstream collecting duct, loop diuretics can
simultaneous NaCl and water administration. cause severe dehydration. Hyponatremia is less common than
with the thiazides (see below), but patients who increase water
B. Acute Renal Failure intake in response to hypovolemia-induced thirst can become
+
Loop agents can increase the rate of urine flow and enhance K excre- hyponatremic with loop agents. Loop agents can cause hypercal-
tion in acute renal failure. However, they cannot prevent or shorten ciuria, which can lead to mild hypocalcemia and secondary hyper-
the duration of renal failure. Loop agents can actually worsen cast for- parathyroidism. On the other hand, loop agents can have the
mation in myeloma and light-chain nephropathy because increased opposite effect (hypercalcemia) in volume-depleted patients who
−
distal Cl concentration enhances secretion of Tamm-Horsfall have another—previously occult—cause for hypercalcemia, such
protein, which then aggregates with myeloma Bence Jones proteins. as metastatic breast or squamous cell lung carcinoma. Long-term