Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Cl− transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15–4) and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as a result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, primary hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are sometimes useful in the prevention of calcium-containing kidney stones caused by hypercalciuria. They may also modestly reduce the risk of osteoporotic fractures.
The action of thiazides depends in part on renal prostaglandin production. As described for loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions.
The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes insipidus. Use of the thiazides in each of these conditions is described below in Clinical Pharmacology of Diuretic Agents.
A. Hypokalemic Metabolic Alkalosis
These toxicities are similar to those observed with loop diuretics (see previous text and Table 15–2).
B. Impaired Carbohydrate Tolerance
Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. It occurs at higher doses of HCTZ (>50 mg/d) and has not been seen with doses of 12.5 mg/d or less. The effect is due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Thiazides have a weak, dose-dependent, off-target effect to stimulate ATP-sensitive K+ channels and cause hyperpolarization of beta cells, thereby inhibiting insulin release. This effect is exacerbated by hypokalemia, and thus thiazide-induced hyperglycemia may be partially reversed with correction of hypokalemia.
C. Hyperlipidemia
Thiazides cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs). These levels may return toward baseline after prolonged use.
D. Hyponatremia
Hyponatremia is an important adverse effect of thiazide diuretics. It is caused by a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. Genetic studies have shown a link between KCNJ1 polymorphism and thiazide-induced hyponatremia.
E. Impaired Uric Acid Metabolism and Gout
Thiazides are the diuretics most associated with development of gout. One large study found that thiazide diuretics only increase the risk of gout in men younger than age 60 years and not in women or older men. The increased risk in this group of patients was found to be only about 1%.
F. Allergic Reactions