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

Fractional excretion of Na + (%)
25.0
20.0
15.0
10.0
5.0
Control
Diseased
Loop diuretic concentration (plasma)
Figure 25–8. Dose-response curve of furosemide in chronic kidney
disease. With chronic kidney disease the dose-response
curve of furosemide and other loop diuretics shifts to the right.
This may occur as a result of impaired proximal tubular secretion
of the diuretic into the tubular lumen. This can occur for at
least two reasons: (1) competition for peritubular uptake and
luminal secretion by organic anions that accumulate in uremia
such as urate and (2) metabolic acidosis.
Chemistry. Inhibitors of Na + -Cl – symport are sulfonamides
(Table 25–5), and many are analogs of 1,2,4-benzothiadiazine-1,1-
dioxide. Because the original inhibitors of Na + -Cl – symport were
benzothiadiazine derivatives, this class of diuretics became known
as thiazide diuretics. Subsequently, drugs that are pharmacologically
similar to thiazide diuretics but are not thiazides were developed
and are called thiazide-like diuretics. The term thiazide
diuretics is used here to refer to all members of the class of
inhibitors of Na + -Cl – symport.
Mechanism and Site of Action. Some studies using
split-droplet and stationary-microperfusion techniques
described reductions in proximal tubule reabsorption
by thiazide diuretics; however, free-flow micropuncture
studies have not consistently demonstrated
increased solute delivery out of the proximal tubule
following administration of thiazides. In contrast,
micropuncture and in situ microperfusion studies
clearly indicate that thiazide diuretics inhibit NaCl
transport in DCT. The DCT expresses thiazide binding
sites and is accepted as the primary site of action of
thiazide diuretics; the proximal tubule may represent a
secondary site of action.
Figure 25–9 illustrates the current model of electrolyte transport
in DCT. As with other nephron segments, transport is powered
by a Na + pump in the basolateral membrane. Free energy in the electrochemical
gradient for Na + is harnessed by an Na + -Cl – symporter
in the luminal membrane that moves Cl – into the epithelial cell
against its electrochemical gradient. Cl – then exits the basolateral
membrane passively by a Cl – channel. Thiazide diuretics inhibit the
Na + -Cl – symporter. In this regard, Na + or Cl – binding to the
Na + -Cl – symporter modifies thiazide-induced inhibition of the symporter,
suggesting that the thiazide-binding site is shared or altered
by both Na + and Cl – .
Using a functional expression strategy (Cl – -dependent Na +
uptake in Xenopus oocytes), Gamba and colleagues (1993) isolated
a cDNA clone from the urinary bladder of the winter flounder that
codes for an Na + -Cl – symporter. This Na + -Cl – symporter is inhibited
by a number of thiazide diuretics (but not by furosemide, acetazolamide,
or an amiloride derivative) and has 12 putative membranespanning
domains, and its sequence is 47% identical to the cloned
dogfish shark rectal gland Na + -K + -2Cl – symporter. Subsequently,
the rat and human Na + -Cl – symporters were cloned. The human
Na + -Cl – symporter has a predicted sequence of 1021 amino acids,
12 transmembrane domains, and 2 intracellular hydrophilic amino
and carboxyl termini and maps to chromosome 16q13. The Na + -Cl –
symporter (called ENCCl or TSC) is expressed predominantly in
kidney and is localized to the apical membrane of DCT epithelial
cells (Bachmann et al., 1995). Expression of the Na + -Cl – symporter
is regulated by aldosterone (Velázquez et al., 1996). Mutations in the
Na + -Cl – symporter cause a form of inherited hypokalemic alkalosis
called Gitelman syndrome (Simon and Lifton, 1998).
Effects on Urinary Excretion. As would be expected
from their mechanism of action, inhibitors of Na + -Cl –
symport increase Na + and Cl – excretion. However, thiazides
are only moderately efficacious (i.e., maximum
excretion of filtered Na + load is only 5%) because
~90% of the filtered Na + load is reabsorbed before
reaching the DCT. Some thiazide diuretics also are
weak inhibitors of carbonic anhydrase, an effect that
increases HCO 3–
and phosphate excretion and probably
accounts for their weak proximal tubular effects.
Like inhibitors of Na + -K + -2Cl – symport, inhibitors of
Na + -Cl – symport increase K + and titratable acid excretion
by the same mechanisms discussed for loop diuresis.
Acute thiazide administration increases uric acid
excretion. However, uric acid excretion is reduced following
chronic administration by the same mechanisms
discussed for loop diuretics. The acute effects of
inhibitors of Na + -Cl – symport on Ca 2+ excretion are
variable; when administered chronically, thiazide
diuretics decrease Ca 2+ excretion. The mechanism
involves increased proximal reabsorption owing to volume
depletion, as well as direct effects of thiazides to
increase Ca 2+ reabsorption in the DCT. Thiazide diuretics
may cause a mild magnesuria by a poorly understood
mechanism, and there is increasing awareness
that long-term use of thiazide diuretics may cause magnesium
deficiency, particularly in the elderly. Since
inhibitors of Na + -Cl – symport inhibit transport in the
cortical diluting segment, thiazide diuretics attenuate
the kidney’s ability to excrete dilute urine during water
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CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME