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

Table 25–2
Inhibitors of Carbonic Anhydrase
RELATIVE ORAL ROUTE OF
DRUG STRUCTURE POTENCY AVAILABILITY t 1/2
(HOURS) ELIMINATION
Acetazolamide CH 3 CONH S SO 2 NH 2 1 ~100% 6-9 R
(DIAMOX)
N N
Dichlorphenamide SO 2 NH 2
30 ID ID ID
(DARAMIDE)
Methazolamide CH 3 CON S SO 2 NH 2
>1; <10 ~100% ~14 ~25%, ~75% M
(GLAUCTABS)
CI
SO 2 NH 2
CI
N N
H 3 C
Abbreviations: R, renal excretion of intact drug; M, metabolism; ID, insufficient data.
epithelial cell, where it reacts with water to form H 2
CO 3
, a reaction
catalyzed by cytoplasmic carbonic anhydrase (Figure 25–6).
Continued operation of the Na + -H + antiporter maintains a low proton
concentration in the cell, so H 2
CO 3
ionizes spontaneously to
Lumen
Na +
(1)
H + (1) A
HCO – 3
H 2 CO 3
CA
CO 2 + H 2 O
CA inhibitors
PROXIMAL TUBULE
H +
H 2 CO 3
Na +
HCO 3
–
CA
CO 2 + H 2 O
Interstitial
space
K + CH
(2) K +
ATPase
(1)
(3)
(3)
Na +
HCO 3
–
LM
BL
Figure 25–6. NaHCO 3
reabsorption in proximal tubule and mechanism
of diuretic action of carbonic anhydrase inhibitors. The
actual reaction catalyzed by carbonic anhydrase is OH – + CO 2
→
HCO 3–
; however, H 2
O → OH – + H + , and HCO 3–
+ H + → H 2
CO 3
,
so the net reaction is H 2
O + CO 2
→ H 2
CO 3
. Numbers in parentheses
indicate stoichiometry. A, antiporter; S, symporter; CH, ion
channel; BL, basolateral membrane; LM, luminal membrane.
S
form H + and HCO 3–
, creating an electrochemical gradient for HCO 3
–
across the basolateral membrane. The electrochemical gradient for
HCO 3–
is used by an Na + -HCO 3–
symporter (also referred to as the
Na + -HCO 3–
co-transporter [NBC]) in the basolateral membrane to
transport NaHCO 3
into the interstitial space. The net effect of this
process is transport of NaHCO 3
from the tubular lumen to the interstitial
space, followed by movement of water (isotonic reabsorption).
Removal of water concentrates Cl – in the tubular lumen, and consequently,
Cl – diffuses down its concentration gradient into the interstitium
by the paracellular pathway.
Carbonic anhydrase inhibitors potently inhibit (IC 50
for acetazolamide
is 10 nM) both the membrane-bound and cytoplasmic
forms of carbonic anhydrase, resulting in nearly complete abolition
of NaHCO 3
reabsorption in the proximal tubule. Studies with a highmolecular-weight
carbonic anhydrase inhibitor that inhibits only
luminal enzyme because of limited cellular permeability indicate
that inhibition of both membrane-bound and cytoplasmic pools of
carbonic anhydrase contributes to the diuretic activity of carbonic
anhydrase inhibitors. Because of the large excess of carbonic anhydrase
in proximal tubules, a high percentage of enzyme activity must
be inhibited before an effect on electrolyte excretion is observed.
Although the proximal tubule is the major site of action of carbonic
anhydrase inhibitors, carbonic anhydrase also is involved in secretion
of titratable acid in the collecting duct system (a process that involves
a proton pump); therefore, the collecting duct system is a secondary
site of action for this class of drugs.
Effects on Urinary Excretion. Inhibition of carbonic
anhydrase is associated with a rapid rise in urinary
HCO 3–
excretion to ~35% of filtered load. This, along
with inhibition of titratable acid and NH 4+
secretion in
the collecting-duct system, results in an increase in urinary
pH to ~8 and development of a metabolic acidosis.