ACTIONS AND MECHANISM
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
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.
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:
with recurrent formation of calcium stones (see Plate 6-3)
insipidus (see Plate 3-27)
adverse effects of thiazide diuretics include:
· 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).
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