DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

nonosmotic vasopressin release, and activation of the
rennin–angiotensin–aldosterone axis.
Acutely, loop diuretics increase uric acid excretion,
whereas chronic administration of these drugs results in
reduced uric acid excretion. Chronic effects of loop
diuretics on uric acid excretion may be due to enhanced
proximal tubule transport or secondary to volume depletion,
leading to increased uric acid reabsorption, or to
competition between diuretic and uric acid for the
organic acid secretory mechanism in proximal tubule,
leading to reduced uric acid secretion. Asymptomatic
hyperuricemia is a common consequence of loop diruetics,
but painful episodes of gout are rarely reported.
By blocking active NaCl reabsorption in the thick
ascending limb, inhibitors of Na + -K + -2Cl – symport
interfere with a critical step in the mechanism that produces
a hypertonic medullary interstitium. Therefore,
loop diuretics block the kidney’s ability to concentrate
urine during hydropenia. Also, since the thick ascending
limb is part of the diluting segment, inhibitors of
Na + -K + -2Cl – symport markedly impair the kidney’s
ability to excrete a dilute urine during water diuresis.
Effects on Renal Hemodynamics. If volume depletion is prevented by
replacing fluid losses, inhibitors of Na + -K + -2Cl – symport generally
increase total RBF and redistribute RBF to the midcortex. However,
the effects on RBF are variable. The mechanism of the increase in
RBF is not known but may involve prostaglandins. Nonsteroidal antiinflammatory
drugs (NSAIDs) attenuate the diuretic response to loop
diuretics in part by preventing prostaglandin-mediated increases in
RBF. Loop diuretics block TGF by inhibiting salt transport into the
macula densa so that the macula densa no longer can detect NaCl concentrations
in the tubular fluid. Therefore, unlike carbonic anhydrase
inhibitors, loop diuretics do not decrease GFR by activating TGF.
Loop diuretics are powerful stimulators of renin release. This effect is
due to interference with NaCl transport by the macula densa and, if
volume depletion occurs, to reflex activation of the sympathetic nervous
system and stimulation of the intrarenal baroreceptor mechanism.
Prostaglandins, particularly prostacyclin, may play an important role
in mediating the renin-release response to loop diuretics.
Other Actions. Loop diuretics may cause direct vascular effects.
Loop diuretics, particularly furosemide, acutely increase systemic
venous capacitance and thereby decrease left ventricular filling pressure.
This effect, which may be mediated by prostaglandins and
requires intact kidneys, benefits patients with pulmonary edema even
before diuresis ensues. Furosemide and ethacrynic acid can inhibit
Na + ,K + -ATPase, glycolysis, mitochondrial respiration, the microsomal
Ca 2+ pump, adenylyl cyclase, phosphodiesterase, and
prostaglandin dehydrogenase; however, these effects do not have
therapeutic implications. In vitro, high doses of inhibitors of
Na + -K + -2Cl – symport can inhibit electrolyte transport in many
tissues. Only in the inner ear, where alterations in the electrolyte
composition of endolymph may contribute to drug-induced ototoxicity,
is this effect important clinically. Irreversible ototoxicity is
more common at high doses, with rapid IV administration, and during
concommitant therapy with other drugs known to be ototoxic (e.g.,
aminoglycoside antibiotics, cisplatin, vancomycin).
Absorption and Elimination. The oral bioavailabilities,
plasma t 1/2
, and routes of elimination of inhibitors of
Na + -K + -2Cl – symport are listed in Table 25–4. Because
furosemide, bumetanide, ethacrynic acid, and torsemide
are bound extensively to plasma proteins, delivery of
these drugs to the tubules by filtration is limited.
However, they are secreted efficiently by the organic
acid transport system in the proximal tubule, and
thereby gain access to their binding sites on the
Na + -K + -2Cl – symport in the luminal membrane of the
thick ascending limb. Probenecid shifts the plasma
concentration-response curve to furosemide to the right
by competitively inhibiting furosemide secretion by the
organic acid transport system.
Approximately 65% of furosemide is excreted unchanged in
urine, and the remainder is conjugated to glucuronic acid in the
kidney. Thus, in patients with renal but not liver disease, the elimination
t 1/2
of furosemide is prolonged. In contrast, bumetanide and
torsemide have significant hepatic metabolism, so the elimination t 1/2
of these loop diuretics are prolonged by liver but not renal disease.
Although average oral availability of furosemide is ~60%,
bioavailability varies (10-100%). In contrast, oral availabilities of
bumetanide and torsemide are reliably high. Heart failure patients
have fewer hospitalizations and better quality of life with torsemide
than with furosemide, perhaps because of its more reliable absorption.
As a class, loop diuretics have short elimination t 1/2
, and prolonged-release
preparations are not available. Consequently, often
the dosing interval is too short to maintain adequate levels of loop
diuretics in the tubular lumen. Note that torsemide has a longer t 1/2
than other agents available in the U.S. (Table 25–4). As the concentration
of loop diuretic in the tubular lumen declines, nephrons begin
to avidly reabsorb Na + , which often nullifies the overall effect of the
loop diuretic on total-body Na + . This phenomenon of “postdiuretic
Na + retention” can be overcome by restricting dietary Na + intake or
by more frequent administration of the loop diuretic (Ellison, 1999).
Furosemide, with its short t 1/2
, often produces a poor response when
administered only once daily, a common clinical error.
Toxicity, Adverse Effects, Contraindications, Drug
Interactions. Adverse effects unrelated to diuretic efficacy
are rare, and most adverse effects are due to abnormalities
of fluid and electrolyte balance. Overzealous
use of loop diuretics can cause serious depletion of
total-body Na + .
This may manifest as hyponatremia and/or extracellular fluid
volume depletion associated with hypotension, reduced GFR, circulatory
collapse, thromboembolic episodes, and in patients with liver
disease, hepatic encephalopathy. Increased Na + delivery to the
distal tubule, particularly when combined with activation of the
rennin–angiotensin system, leads to increased urinary K + and H +
excretion, causing a hypochloremic alkalosis. If dietary K + intake
is not sufficient, hypokalemia may develop, and this may induce
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CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME