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

Table 25–1
Excretory and Renal Hemodynamic Effects of Diuretics a
Diuretic Mechanism CATIONS ANIONS URIC ACID RENAL HEMODYNAMICS
(Primary site of action) Na + K + H +b Ca 2+ Mg 2+ Cl – – –
HCO 3
H 2
PO 4
Acute Chronic RBF GFR FF TGF
Inhibitors of CA + ++ – NC V (+) ++ ++ I – – – NC +
(proximal tubule)
Osmotic diuretics ++ + I + ++ + + + + I + NC – I
(loop of Henle)
Inhibitors of ++ ++ + ++ ++ ++ + c + c + – V(+) NC V(–) –
Na + -K + -2Cl −
symport (thick
ascending limb)
Inhibitors of Na + -Cl − + ++ + V(–) V(+) + + c + c + – NC V(–) V(–) NC
symport (distal
convoluted tubule)
Inhibitors of renal + – – – – + (+) NC I – NC NC NC NC
epithelial Na +
channels (late distal
tubule, collecting
duct)
Antagonists of + – – I – + (+) I I – NC NC NC NC
mineralocorticoid
receptors (late distal
tubule, collecting
duct)
a
Except for uric acid, changes are for acute effects of diuretics in the absence of significant volume depletion, which would trigger complex physiological
adjustments. b H + , titratable acid and NH 4+
. c In general, these effects are restricted to those individual agents that inhibit carbonic anhydrase.
However, there are notable exceptions in which symport inhibitors increase bicarbonate and phosphate (e.g., metolazone, bumetanide).
++, +, (+),−, NC, V, V(+), V(−) and I indicate marked increase, mild to moderate increase, slight increase, decrease, no change, variable effect, variable
increase, variable decrease, and insufficient data, respectively. For cations and anions, the indicated effects refer to absolute changes in fractional
excretion.
RBF, renal blood flow; GFR, glomerular filtration rate; FF, filtration fraction; TGF, tubuloglomerular feedback; CA, carbonic anhydrase.
Chemistry. When sulfanilamide was introduced as a chemotherapeutic
agent, metabolic acidosis was recognized as a side effect. This
observation led to the demonstration that sulfanilamide is an inhibitor
of carbonic anhydrase. Subsequently, an enormous number of sulfonamides
were synthesized and tested for their ability to inhibit carbonic
anhydrase; of these compounds, acetazolamide has been studied most
extensively. There are three orally administered carbonic anhydrase
inhibitors—acetazolamide, dichlorphenamide (not marketed
in the U.S.), and methazolamide. The common molecular motif of
available carbonic anhydrase inhibitors is an unsubstituted sulfonamide
moiety (Table 25–2).
Mechanism and Site of Action. Proximal tubular
epithelial cells are richly endowed with the zinc metalloenzyme
carbonic anhydrase, which is found in the
luminal and basolateral membranes (type IV carbonic
anhydrase, an enzyme tethered to the membrane by a
glycosylphosphatidylinositol linkage), as well as in the
cytoplasm (type II carbonic anhydrase). Carbonic anhydrase
plays a key role in NaHCO 3
reabsorption and acid
secretion.
In the proximal tubule, the free energy in the Na + gradient
established by the basolateral Na + pump is used by an Na + -H +
antiporter (also referred to as an Na + -H + exchanger [NHE]) in the
luminal membrane to transport H + into the tubular lumen in
exchange for Na + (Figure 25–6). In the lumen, H + reacts with
filtered HCO 3–
to form H 2
CO 3
, which decomposes rapidly to CO 2
and water in the presence of carbonic anhydrase in the brush border.
Normally, the reaction occurs slowly, but carbonic anhydrase
reversibly accelerates this reaction several thousand times. CO 2
is
lipophilic and rapidly diffuses across the luminal membrane into the