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Saturday, February 6, 2021




In the distal convoluted tubule, Na+ and Cl are reabsorbed across the apical surface of the tubular epithelium on NCC symporters. The thiazide diuretics enter the nephron through the organic anion pathway in the proximal tubule, then they bind to the apical surface of NCC symporters and inhibit them.

Because the vast majority of Na+ reabsorption occurs in earlier nephron segments, particularly the proximal tubule and thick ascending limb, thiazides induce only a modest degree of natriuresis. Some agents, however, are also weak carbonic anhydrase inhibitors (see Plate 10-2) and thus partially inhibit Na+ reabsorption in the proximal tubule.

Plate 10-4

Thiazides also affect the handling of several other ions. For example, they promote kaliuresis through numerous mechanisms. First, the increased Na+ load that reaches the cortical collecting duct leaves a negative charge in the lumen as it is reabsorbed, which promotes K+ secretion through apical ROM-K channels. Second, the increased urine fl ow through the cortical collecting duct up-regulates apical maxi-K channels. Finally, volume losses lead to aldosterone release, which further increases distal K+ (and H+) secretion.

Thiazides also enhance calcium reabsorption through several mechanisms. First, blockade of NCC transport decreases intracellular Na+ concentrations, increasing the gradient for basolateral Na+/Ca2+ exchange. Second, volume losses stimulate reabsorption of Na+ and Cl in the proximal tubule, enhancing the gradient for para-cellular calcium reabsorption. (For a detailed discussion of calcium handling in the nephron, see Plate 3-11.) Thiazides also inhibit magnesium reabsorption, likely by interfering with TRPM6-mediated reabsorption in the distal nephron, although the exact mechanism remains unknown.

Finally, thiazides decrease excretion of uric acid. Like the loop diuretics, thiazides likely exert this effect by increasing proximal tubular reabsorption (secondary to fluid depletion) and decreasing proximal tubular secretion (by competing with uric acid on the organic cation secretion pathway).



The major thiazide and thiazide-like diuretics are listed in the plate.


The major indications for thiazide diuretics include:

·      Edema

·      Hypertension

·      Hypocalcemia

·      Hypercalciuria with recurrent formation of calcium stones (see Plate 6-3)

·      Diabetes insipidus (see Plate 3-27)



The major adverse effects of thiazide diuretics include:

·      Hypokalemia

·   Hyponatremia. By inhibiting solute reabsorption in the distal nephron, thiazides prevent maximal urine dilution. In addition, significant fluid losses can trigger release of antidiuretic hormone (see Plate 3-17).

·      Hypercalcemia

·      Hypomagnesemia use)

·      Hyperuricemia, which may precipitate gout attacks

·    Metabolic alkalosis, resulting from aldosterone release secondary to volume losses and, if hypokalemia is present, an increase in proximal tubular ammoniagenesis

· Impaired glucose tolerance or diabetes mellitus secondary to multiple mechanisms, including catecholamine release (secondary to activation of the sympathetic nervous system resulting from volume depletion), as well as reduced insulin secretion (secondary to hypokalemia)

·      Hyperlipidemia, through mostly unknown mechanisms

·      Nausea and vomiting

·      Photosensitivity

·      Erectile dysfunction

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