Because Henle’s loop is indirectly responsible for water reabsorption by the downstream collecting duct, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become hyponatremic with loop agents. Loop agents can cause hypercalciuria, which can lead to mild hypocalcemia and secondary hyperparathyroidism. On the other hand, loop agents can have the opposite effect (hypercalcemia) in volume-depleted patients who have another—previously occult—cause for hypercalcemia, such as metastatic breast or squamous cell lung carcinoma. Long-term loop diuretic therapy may worsen thiamine deficiency in patients with heart failure. Intravenous bumetanide administration has rarely caused injection site superficial tenderness of the skin, an effect not seen with other loop diuretics.
Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare. Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure.
The thiazide diuretics were discovered in 1957, as a result of efforts to synthesize more potent carbonic anhydrase inhibitors. It subsequently became clear that the thiazides inhibit NaCl, rather than NaHCO3− transport and that their action is predominantly in the DCT, rather than the PCT. Some members of this group retain significant carbonic anhydrase inhibitory activity (eg, chlorthalidone). The prototypical thiazide is hydrochlorothiazide (HCTZ).
Like carbonic anhydrase inhibitors and three loop diuretics, all of the thiazides have an unsubstituted sulfonamide group (Figure 15–8).
FIGURE 15–8 Hydrochlorothiazide and related agents.
TABLE 15–6 Thiazides and related diuretics.
1Not a thiazide but a sulfonamide qualitatively similar to the thiazides.
All thiazides can be administered orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. HCTZ is considerably more potent and should be used in much lower doses (Table 15–6). Chlorthalidone is slowly absorbed and has a longer duration of action. Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT. All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result, thiazide use may blunt uric acid secretion and elevate serum uric acid level.