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

680 However, even with a high degree of inhibition of carbonic
anhydrase, 65% of HCO 3–
is rescued from excretion
by poorly understood mechanisms that may
involve carbonic anhydrase-independent HCO 3–
reabsorption
at downstream sites. Inhibition of the transport
mechanism described in the preceding section results
in increased delivery of Na + and Cl – to the loop of
Henle, which has a large reabsorptive capacity and captures
most of the Cl – and a portion of the Na + . Thus only
a small increase in Cl – excretion occurs, HCO 3–
being
the major anion excreted along with the cations Na + and
K + . The fractional excretion of Na + may be as much as
5%, and the fractional excretion of K + can be as much
as 70%. The increased excretion of K + is in part secondary
to increased delivery of Na + to the distal
nephron. The mechanism by which increased distal Na +
delivery enhances K + excretion is described in the section
on inhibitors of Na + channels.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Other mechanisms contributing to enhanced K + excretion
include flow-dependent enhancement of K + secretion by the collecting
duct, nonosmotic vasopressin release, and activation of the reninangiotensin-aldosterone
axis. Carbonic anhydrase inhibitors increase
phosphate excretion (mechanism unknown) but have little or no
effect on Ca 2+ or Mg 2+ excretion. The effects of carbonic anhydrase
inhibitors on renal excretion are self-limiting, probably because the
resulting metabolic acidosis decreases the filtered load of HCO 3–
to
the point that the uncatalyzed reaction between CO 2
and water is
sufficient to achieve HCO 3–
reabsorption. Studies in rabbits show
that the K i
for luminal carbonic anhydrase inhibition in outer medulla
is increased >100-fold over the concentration required in control
tubules. These results suggest that acidosis induces a conformational
change in the protein making it less sensitive to inhibition by acetazolamide
(Tsuroka, 1998).
Effects on Renal Hemodynamics. By inhibiting proximal
reabsorption, carbonic anhydrase inhibitors increase
delivery of solutes to the macula densa. This triggers
TGF, which increases afferent arteriolar resistance and
reduces renal blood flow (RBF) and glomerular filtration
rate (GFR).
Other Actions. Carbonic anhydrase is present in a number of
extrarenal tissues, including the eye, gastric mucosa, pancreas,
central nervous system (CNS), and erythrocytes. Carbonic anhydrase
in the ciliary processes of the eye mediates formation of large amounts
of HCO 3–
in aqueous humor. Inhibition of carbonic anhydrase
decreases the rate of formation of aqueous humor and consequently
reduces intraocular pressure. Acetazolamide frequently causes paresthesias
and somnolence, suggesting an action of carbonic anhydrase
inhibitors in the CNS. The efficacy of acetazolamide in epilepsy is due
in part to the production of metabolic acidosis; however, direct actions
of acetazolamide in the CNS also contribute to its anticonvulsant
action. Owing to interference with carbonic anhydrase activity in erythrocytes,
carbonic anhydrase inhibitors increase CO 2
levels in
peripheral tissues and decrease CO 2
levels in expired gas. Large doses
of carbonic anhydrase inhibitors reduce gastric acid secretion, but this
has no therapeutic application. Acetazolamide causes vasodilation by
opening vascular Ca 2+ -activated K + channels; however, the clinical
significance of this effect is unclear.
Absorption and Elimination. Carbonic anhydrase
inhibitors are avidly bound by carbonic anhydrase, and
accordingly, tissues rich in this enzyme will have higher
concentrations of carbonic anhydrase inhibitors following
systemic administration. See Table 25–2 for structures
and pharmacokinetic data.
Toxicity, Adverse Effects, Contraindications, Drug Interactions.
Serious toxic reactions to carbonic anhydrase inhibitors are infrequent;
however, these drugs are sulfonamide derivatives and, like
other sulfonamides, may cause bone marrow depression, skin toxicity,
sulfonamide-like renal lesions, and allergic reactions in patients
hypersensitive to sulfonamides. With large doses, many patients
exhibit drowsiness and paresthesias. Most adverse effects, contraindications,
and drug interactions are secondary to urinary alkalinization
or metabolic acidosis, including:
• diversion of ammonia of renal origin from urine into the systemic
circulation, a process that may induce or worsen hepatic
encephalopathy (the drugs are contraindicated in patients with
hepatic cirrhosis)
• calculus formation and ureteral colic owing to precipitation of
calcium phosphate salts in an alkaline urine
• worsening of metabolic or respiratory acidosis (the drugs are contraindicated
in patients with hyperchloremic acidosis or severe
chronic obstructive pulmonary disease)
• reduction of the urinary excretion rate of weak organic bases
Therapeutic Uses. Although acetazolamide is used for
treatment of edema, the efficacy of carbonic anhydrase
inhibitors as single agents is low, and carbonic anhydrase
inhibitors are not employed widely in this regard.
The combination of acetazolamide with diuretics that
block Na + reabsorption at more distal sites in the
nephron causes a marked natriuretic response in patients
with low basal fractional excretion of Na + (<0.2%) who
are resistant to diuretic monotherapy (Knauf and
Mutschler, 1997). Even so, the long-term usefulness of
carbonic anhydrase inhibitors often is compromised by
the development of metabolic acidosis.
The major indication for carbonic anhydrase inhibitors is
open-angle glaucoma. Two products developed specifically for this
use are dorzolamide (TRUSOPT, others) and brinzolamide (AZOPT),
which are available only as ophthalmic drops. Carbonic anhydrase
inhibitors also may be employed for secondary glaucoma and preoperatively
in acute angle-closure glaucoma to lower intraocular pressure
before surgery (Chapter 64). Acetazolamide also is used for the
treatment of epilepsy (Chapter 21). The rapid development of tolerance,
however, may limit the usefulness of carbonic anhydrase
inhibitors for epilepsy.