Osmotic Diuretics

cose (the product of GFR and plasma glucose) exceeds the maximal glucose reabsorptive capacity of the proximal tubule, resulting in a glucose diuresis. In this setting, glucose acts as a nonabsorbable osmolyte. Similarly, radiocontrast agents such as sodium iothalamate, iopamidol, or sodium methylglucamine ioxaglate may also promote an osmotic diuresis by virtue of their limited transport in the nephron. Practically speaking, however, few osmotic diuretics are available for therapeutic use. The prototype is mannitol (Osmitrol), a nonme-tabolizable polysaccharide derivative of sucrose. Other clinically available osmotic diuretics include glycerin (glycerol, Osmoglyn, and the topical agent Ophthalgan), isosorbide Osmotic) (not to be confused with its derivative, isosorbide dinitrate, an antianginal drug), and urea (Ureaphil, Urevert). The chemical structures of these compounds are shown in Fig. 2.

The ability of mannitol and other osmotic diuretics to reduce solute and fluid absorption depends primarily on the high water permeability of proximal tubules and thin descending limbs of Henle's loop. In proximal tubules, solute transport proceeds in an isosmotic fashion with sodium and water being absorbed in a fixed ratio; the tubular fluid remains at virtually the same tonicity as the surrounding interstitial fluid. Mannitol is freely filtered at the glomerulus and contributes to the total solute concentration of the luminal fluid. In this setting, sodium and fluid absorption proceed normally. However, mannitol is not transported and since the fluid remains isosmotic, the concentration of h h oh oh mannitol (Osmitrol) hoh2C—'

ch2oh lili oh oh h h glycerin (Glycerol, Osmoglyn) oh'CxC''CN

¿h oh h isosorbide (Ismotic)

urea (Ureaphil, Urevert)

FIGURE 2. Chemical structures h2n—c—nh2 o of representative osmotic diuretics.

FIGURE 3. Model for solute and fluid reabsorption in the proximal tubule, (a) Sodium transport is mediated by Na+/H+ exchange (1), Na+-coupled cotransport (2), and by other electroneutral transporters (3). Osmotic diuretics such as mannitol nonspecifically inhibit fluid absorption by retaining water in the lumen, (b) Carbonic anhydrase inhibitors (1) block the dehydration of H2C03, which accumulates in the lumen, thereby limiting the secretion of H+ions by the Na+/H+ exchanger (2).

FIGURE 3. Model for solute and fluid reabsorption in the proximal tubule, (a) Sodium transport is mediated by Na+/H+ exchange (1), Na+-coupled cotransport (2), and by other electroneutral transporters (3). Osmotic diuretics such as mannitol nonspecifically inhibit fluid absorption by retaining water in the lumen, (b) Carbonic anhydrase inhibitors (1) block the dehydration of H2C03, which accumulates in the lumen, thereby limiting the secretion of H+ions by the Na+/H+ exchanger (2).

mannitol increases as the tubular sodium concentration decreases, thereby producing an initial dissociation between sodium and fluid absorption (see Fig. 3).

Mannitol in the tubular lumen diminishes net fluid absorption, while the continued absorption of sodium lowers its concentration in the lumen until a limiting gradient is established, against which sodium is no longer absorbed. Similar physical-chemical effects are responsible for reduced fluid absorption by thin descending limbs of Henle's loop, where osmotic water permeability is as great as in proximal tubules. In contrast to proximal tubules, however, sodium absorption is negligible in thin descending limbs. Therefore the action of osmotic diuretics in water-permeable thin limbs is simply to retard fluid absorption without an effect on sodium transport. The overall consequence of mannitol administration is to augment the rate of urine flow, with relatively modest increases of sodium excretion and, notably, without the intense loss of potassium that accompanies the action of diuretics that directly inhibit sodium transport by thick ascending limbs or distal convoluted tubules.

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