Thiazides

THIAZIDES

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 was predominantly in the DCT, rather than the PCT. Some members of this group retain significant carbonic anhydrase inhibitory activity (eg, chlor-thalidone). The prototypical thiazide is hydrochlorothiazide(HCTZ).

Chemistry & Pharmacokinetics

Like carbonic anhydrase inhibitors and three loop diuretics, all of the thiazides have an unsubstituted sulfonamide group (Figure 15–8).

All thiazides can be administered orally, but there are differ-ences 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 adminis-tration. HCTZ is considerably more potent and should be used in much lower doses (Table 15–5). 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 secre-tion and elevate serum uric acid level.

Pharmacodynamics

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 deple-tion 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 mem-brane (Figure 15–4), and increases overall reabsorption of Ca²⁺. Although thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria.

The action of thiazides depends in part on renal prostaglandin production. As described for loop diuretics, the actions of thia-zides can also be inhibited by NSAIDs under certain conditions.

Clinical Indications & Dosage (Table 15–5)

The major indications for thiazide diuretics are (1) hypertension, heart failure, (3) nephrolithiasis due to idiopathic hypercalci-uria, and (4) nephrogenic diabetes insipidus. Use of the thiazides in each of these conditions is described below in Clinical Pharmacology of Diuretic Agents.

Toxicity

A. Hypokalemic Metabolic Alkalosis and Hyperuricemia

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. The effect is due to both impaired pancreatic release of insulin and dimin-ished tissue utilization of glucose. Hyperglycemia may be partially reversible 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.

E. Allergic Reactions

The thiazides are sulfonamides and share cross-reactivity with other members of this chemical group. Photosensitivity or gener-alized dermatitis occurs rarely. Serious allergic reactions are extremely rare but do include hemolytic anemia, thrombocytope-nia, and acute necrotizing pancreatitis.

F. Other Toxicities

Weakness, fatigability, and paresthesias similar to those of car-bonic anhydrase inhibitors may occur. Impotence has been reported but is probably related to volume depletion.

Contraindications

Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure (see text that follows).