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Diuresis and Diuretics

Increases in urine excretion above 1 mL/min (diuresis) can have the following causes:

♦ Water diuresis: Decreases in plasma osmolality and/or an increased blood volume lead to the reduction of ADH levels and, thus, to the excretion of "free water" (^ p. 164).

♦ Osmotic diuresis results from the presence of non-reabsorbable, osmotically active substances (e.g., mannitol) in the renal tubules. These substances retain H2O in the tubule lumen, which is subsequently excreted. Osmotic diuresis can also occur when the concentration of an reabsorbable substance (e.g., glucose) exceeds its tubular reabsorption capacity resulting, for example, in hypergly-cemia (^ p. 158). The glucosuria occurring in diabetes mellitus is therefore accompanied by diuresis and a secondary increase in thirst. Hy-perbicarbonaturia can lead to osmotic diuresis to the same reason (^ p. 176).

♦ Pressure diuresis occurs when osmolality in the renal medulla decreases in the presence of increased renal medullary blood flow due, in most cases, to hypertension (^ p. 170).

♦ Diuretics (^ A) are drugs that induce diuresis. Most of them (except osmotic diuretics like mannitol) work primarily by inhibiting NaCl reabsorption (saluretics) and, secondarily, by decreasing water reabsorption. The goal of therapeutic diuresis, e.g., in treating edema and hypertension, is to reduce the ECF volume.

Although diuretics basically inhibit NaCl transport throughout the entire body, they have a large degree of renal "specificity" because they act from the tubular lumen, where they become highly concentrated due to tubular secretion (^ p. 160) and tubular water reabsorption. Therefore, dosages that do not induce unwanted systemic effects are therapeutically effective in the tubule lumen.

Diuretics of the carbonic anhydrase inhibitor type (e.g., acetazolamide, benzolamide) decrease Na+/H+ exchange and HCO3- reabsorption in the proximal tubule (^ p. 174ff.). The overall extent of diuresis achieved is small because more distal segments of the tubule reabsorb the NaCl not reabsorbed upstream and because the GFR decreases due to tubuloglomerular feedback, TGF (^ p. 184). In addition, increased HCO3- excretion also leads to non-respiratory (metabolic) acidosis. Therefore, this type of diuretic is used only in patients with concomitant alkalosis.

Loop diuretics (e.g., furosemide and bumetanide) are highly effective. They inhibit the bumetanide-sensitive co-transporter BSC (^ p. 162 B6), a Na+-2Cl-K+ symport carrier, in the thick ascending limb (TAL) of the loop of Henle. This not only decreases NaCl reabsorption there, but also stalls the "motor" on the concentration mechanism (^ p. 166). Since the lumen-positive transepithelial potential (LPTP) in the TAL also falls (^ p. 162 B7), para-cellular reabsorption of Na+, Ca2+ and Mg2+ is also inhibited. Because increasing amounts of non-reabsorbed Na+ now arrive at the collecting duct (^ p. 181 B3), K+ secretion increases and the simultaneous loss of H+ leads to hypo-kalemia and hypokalemic alkalosis.

Loop diuretics inhibit BSC at the macula densa, thereby "tricking" the juxtaglomerular apparatus (JGA) into believing that no more NaCl is present in the tubular lumen. The GFR then rises as a result of the corresponding tubuloglomerular feedback (^ p. 184), which further promotes diuresis.

Thiazide diuretics inhibit NaCl resorption in the distal tubule (TSC, ^ p. 162 B8). Like loop diuretics, they increase Na+ reabsorption downstream, resulting in losses of K+ and H+.

Potassium-sparing diuretics. Amiloride block Na+ channels in the principal cells of the connecting tubule and collecting duct, leading to a reduction ofK+ excretion. Aldosterone antagonists (e.g., spironolactone), which block the cytoplasmic aldosterone receptor, also have a potassium-sparing effect.

Disturbances of Salt and Water Homeostasis

When osmolality remains normal, disturbances of salt and water homeostasis (^ B and p. 170) only affect the ECF volume (^ B1 and 4). When the osmolality of the ECF increases (hyperosmolality) or decreases (hypo-osmolality), water in the extra- and intracellular compartments is redistributed (^ B2, 3, 5, 6). The main causes of these disturbances are listed in B (orange background). The effects of these disturbances are hypovolemia in cases 1, 2 and 3, intracellular edema (e.g., swelling of the brain) in disturbances 3 and 5, and extracellular edema (pulmonary edema) in disturbances 4, 5 and 6.

i— A. Site of action of diuretics

Carbonic anhydrase inhibitors

(e.g., acetazolamide)

Na+ and HCO3 reabsorption

Na+ and HCO3 reabsorption

Na+-Cl symport

Aldosterone antagonists

(e.g., spironolactone)

Na+ channel (indirect effect)


Na+ channel (direct effect)

NaCl reabsorption^ H2O reabsorption^

Na+-Cl symport

Aldosterone antagonists

(e.g., spironolactone)

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