Page 274 - Basic _ Clinical Pharmacology ( PDFDrive )

260 SECTION III Cardiovascular-Renal Drugs

to CO at the luminal membrane and rehydration of CO to TABLE 15–3 Carbonic anhydrase inhibitors used
2
2
H CO in the cytoplasm as previously described. By blocking orally in the treatment of glaucoma.
3
2
carbonic anhydrase, inhibitors blunt NaHCO reabsorption and
3
cause diuresis. Drug Usual Oral Dosage
Carbonic anhydrase inhibitors were the forerunners of mod- Dichlorphenamide 50 mg 1–3 times daily
ern diuretics. They were discovered in 1937 when it was found Methazolamide 50–100 mg 2–3 times daily
that bacteriostatic sulfonamides caused an alkaline diuresis and
hyperchloremic metabolic acidosis. With the development of
newer agents, carbonic anhydrase inhibitors are now rarely used
as diuretics, but they still have several specific applications that are at sites other than the kidney. The ciliary body of the eye secretes
−
discussed below. The prototypical carbonic anhydrase inhibitor is HCO from the blood into the aqueous humor. Likewise, forma-
3
acetazolamide. tion of cerebrospinal fluid (CSF) by the choroid plexus involves
−
−
HCO secretion. Although these processes remove HCO from
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3
Pharmacokinetics the blood (the direction opposite of that in the proximal tubule),
they are similarly inhibited by carbonic anhydrase inhibitors.
The carbonic anhydrase inhibitors are well absorbed after oral
−
administration. An increase in urine pH from the HCO diuresis Clinical Indications & Dosage (Table 15–3)
3
is apparent within 30 minutes, is maximal at 2 hours, and persists
for 12 hours after a single dose. Excretion of the drug is by secre- A. Glaucoma
tion in the proximal tubule S segment. Therefore, dosing must be The reduction of aqueous humor formation by carbonic anhy-
2
reduced in renal insufficiency. drase inhibitors decreases the intraocular pressure. This effect
is valuable in the management of glaucoma in some patients,
Pharmacodynamics making it the most common indication for use of carbonic
anhydrase inhibitors (see Table 10–3). Topically active agents,
Inhibition of carbonic anhydrase activity profoundly depresses which reduce intraocular pressure without producing renal or
−
HCO reabsorption in the PCT. At maximal safe inhibitor dos- systemic effects, are available (dorzolamide, brinzolamide).
3
−
age, 85% of the HCO reabsorptive capacity of the superficial
3
−
PCT is inhibited. Some HCO can still be absorbed at other B. Urinary Alkalinization
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nephron sites by carbonic anhydrase–independent mechanisms, Uric acid and cystine are relatively insoluble and may form stones
so the overall effect of maximal acetazolamide dosage is only about in acidic urine. Therefore, in cystinuria, a disorder of cystine reab-
−
45% inhibition of whole kidney HCO reabsorption. Neverthe- sorption, solubility of cystine can be enhanced by increasing urinary
3
−
less, carbonic anhydrase inhibition causes significant HCO losses pH to 7–7.5 with carbonic anhydrase inhibitors. In the case of uric
3
and hyperchloremic metabolic acidosis (Table 15–2). Because acid, pH needs to be raised only to 6–6.5. In the absence of HCO
−
−
of reduced HCO in the glomerular filtrate and the fact that administration, these effects of acetazolamide last only 2–3 days,
3
3
−
HCO depletion leads to enhanced NaCl reabsorption by the so prolonged therapy requires oral HCO . As a result, these agents
−
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remainder of the nephron, the diuretic efficacy of acetazolamide have proved to be of limited utility for this indication.
decreases significantly with use over several days.
At present, the major clinical applications of acetazolamide
−
involve carbonic anhydrase–dependent HCO and fluid transport C. Metabolic Alkalosis
3
Metabolic alkalosis is generally treated by correction of abnormali-
+
ties in total body K , intravascular volume, or mineralocorticoid
TABLE 15–2 Changes in urinary electrolyte patterns levels. However, when the alkalosis is due to excessive use of diuret-
and body pH in response to diuretic ics in patients with severe heart failure, replacement of intravascular
drugs. volume may be contraindicated. In these cases, acetazolamide can
be useful in correcting the alkalosis as well as producing a small
Urinary Electrolytes additional diuresis for correction of volume overload. Acetazol-
Group NaCl NaHCO 3 K + Body pH amide can also be used to rapidly correct the metabolic alkalosis
that may appear following the correction of respiratory acidosis.
Carbonic anhydrase + +++ + ↓
inhibitors D. Acute Mountain Sickness
Loop agents ++++ 0 + ↑
Weakness, dizziness, insomnia, headache, and nausea can occur
Thiazides ++ + + ↑
in mountain travelers who rapidly ascend above 3000 m. The
Loop agents plus +++++ + ++ ↑ symptoms are usually mild and last for a few days. In more seri-
thiazides
ous cases, rapidly progressing pulmonary or cerebral edema can
+
K -sparing agents + (+) − ↓ be life-threatening. By decreasing CSF formation and by decreas-
+, increase; −, decrease; 0, no change; ↓, acidosis; ↑, alkalosis. ing the pH of the CSF and brain, acetazolamide can increase