Site 1 Diuretics Carbonic Anhydrase Inhibitors

The clinically available CA inhibitors are absorbed well from the ga.slroinlesiinal tract, are distributed to the sites of major importance for CA inhibition, undeigo little, if any biotransformalion. and are excreted primarily by the kidneys. All CA inhibitors attain relatively high concentrations in renal luminal fluid (by a combination of glomerular filtration and active tubular. secretion) and in proximal tuhule eells. 

CA is located both intracellularly (type II CA) and in the luminal bru.sh border membrane (type IV CA) of proximal convoluted tubule cells (Fig. 18-3A). Both of these site I locations are major targets of the CA inhibitors. This group of diuretics also inhibits intracellular CA in the intercalated cells of the connecting and cortical collecting tubules (i.e.. site 4 Fig. 18-6). 

During the first 4 to 7 days of continuous therapy with a CA inhibitor, several noteworthy events occur that lead to an increase in Na and HCO excretion (a) inhibition of the intracellular CA in proximal tubule cells decreases the available H normally exchanged for luminal fluid Na. thus decreasing proximal tubule rcabsorption of Na (Fig. 18-3) and (b) inhibition of CA on the luminal brush border membrane of proximal tubule cells causes a decrease in the production of carbon dioxide within the luminal fluid and a decrease in the proximal tubule uptake of carbon dioxide. 11ie net result is a decrease in the reabsorption of HCO.i. One might a.ssutne that a ma.ssivc diuresis would follow inhibition of the portion of proximal tubule Na reabsorption under the control of CA (i.e.. one third of the 6.5% of the filtered load of Na normally reabsorbed from the proximal luminal fluid, or about 22% of the filtered load of Na ). However. Na rcab.soiption sites downstream (e.specially site 2) compensate for such an action by reabsorbing much of the additional Na presented to them. Some of the luminal fluid HCOj is reabsorbed downstream by a non-CA-mediated sy.stem. Thus, the actions of the CA inhibitors ultimately result in the urinary lo.ss of only 2 to 

Secondarily, the CA inhibilorK enhance the urinary excretion of a substantial amount of K The urinary loss of increases because the proximal tubule actions of CA inhibitors present a greater percentage of the filtered load of Na to site 4. increase the flow rate of luminal fluid through the distal convoluted tubule and collecting tubule, and decrease the availability of intracellular H at site 4. All three changes favor enhanced exchange of luminal fluid Na for intracellular K at site 4. The urinary concentration of Cl actually decreases after the administration of CA in- 

Toward the end of the first week of continuous thmjr with a CA inhibitor, resistance develops to its diuretic ti feci. This is primarily due lo two factors. First, there s. marked reduction in the filtered load of HCOr because ib CA inhibitors produce both a 2O0f reduction in the Gfl via the tubuloglomerular feedback mechanism, and a Rste-tion in the plasma concentration of HCO3. When Iheit less HC0.3 present in the luminal fluid, there is less HCO reabsorption to inhibit. Second, the metabolic acklixsiscn ated by these diuretics provides a sufficient amouni it 

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The answer is c. (Hardman, pp 6917 693 J Acetazolamide is a carbonic anhydrase inhibitor with its primary site of action at the proximal tubule of the nephron. Acetazolamide promotes a urinary excretion of Na, K, and bicarbonate There is a decrease in loss of Cl ions The increased excretion of bicarbonate makes the urine alkaline and may produce metabolic acidosis as a consequence of the loss of bicarbonate from the blood. None of the other diuretic drugs promote a reduction in the excretion of the Cl ion... 

Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are sodium bicarbonate and sodium chloride. Of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHC03 reabsorption) acts predominantly in the proximal tubule. In view of the large quantity of sodium chloride absorbed in the proximal tubule, a drug that specifically blocked reabsorption of this salt at this site might be a particularly powerful diuretic agent. No such drug is currently available. 

Figure 10.1 Sites and mechanisms of action of diuretics. The location of each cell type along the nephron is indicated by the shading patterns. Spironoiactone (not shown) is a competitive aldosterone antagonist and acts primarily in the collecting duct. PT, proximal tubule LH, loop of Henie TAL, thick ascending limb DT, distal tubule DCT, distal convoluted tubule CD, collecting duct PC, principal cell CA, carbonic anhydrase CAI, carbonic anhydrase inhibitors , primary active transport. (Adapted with permission from Ellison D H 1991 The physiologic basis of diuretic synergism its role in treating diuretic resistance. Annals of Internal Medicine 114 886-894.)...

THERAPEUTIC USES The efficacy of carbonic anhydrase inhibitors as single agents for the treatment of edema is low. However, 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. Even so, the long-term usefulness of carbonic anhydrase inhibitors often is compromised by the development of metabohc acidosis. 

The diuretics currently in use today (Table 27.1) are classified by their chemical class (thiazides), mechanism of action (carbonic anhydrase inhibitors and osmotics), site of action (loop diuretics), or effects on urine contents (potassium-sparing diuretics). These drugs vary widely in their efficacy (i.e., their ability to increase the rate of urine formation) and their site of action within the nephron. Efficacy often is measured as the ability of the diuretic to increase the excretion of sodium ions filtered at the glomerulus (i.e., the filtered load of sodium) and should not be confused with potency, which is the amount of the diuretic required to produce a specific diuretic response. 

Efficacy is determined, in part, by the site of action of the diuretic. Drugs (e g., carbonic anhydrase inhibitors) that act primarily on the proximal convoluted tubule to induce diuresis are weak diuretics because of the ability of the nephron to reabsorb a significant portion of the luminal contents in latter portions of the nephron. Likewise dmgs (potassium-spann diureti ... 

Anatomical sites of action - The diuretic action of carbonic anhydrase inhibitors (CAI) generally has been thought to be exerted in the proximal tubule. Micropuncture evidence for reduced HC03" reabsorption in this segment is reasonably firm31,32 although evidence for reduction in Na+ and volume reabsorption is less clear . The best argument for a proximal tub-... 

Strong inhibitors of CA are mostly aromatic sulfonamides.Acetazolamide (19), with K of 6 nM against human carbonic anhydrase II (HCA II), is therapeutically prescribed as a diuretic drug. " The X-ray crystal-structure analysis of the HCA Il-acetazolamide complex confirmed that the V-deprotonated amide binds to in the active site (20) (Scheme 23). ... 

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