Distal Convoluted Tubule

FIGURE 28-4 NaCl reabsorption in distal convoluted tubule and mechanism of diuretic action of Na+—Cl~ symport inhibitors. S, symporter; CH, ion channel. Numbers in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively.

diluted urine during water diuresis. However, since the DCT is not involved in the mechanism that generates a hypertonic medullary interstitium, thiazide diuretics do not alter the kidney's ability to concentrate urine during hydropenia.

In general, inhibitors of Na+-Cl- symport do not affect RBF and only variably reduce GFR owing to increases in intratubular pressure. Since thiazides act at a point past the macula densa, they have little or no influence on TGF.

ABSORPTION AND ELIMINATION The relative potency, oral bioavailability, plasma t1/2, and route of elimination of inhibitors of Na+-Cl- symport are listed in Table 28-5. Of special note is the wide range of half-lives for this class of drugs. Sulfonamides are organic acids and therefore are secreted into the proximal tubule by the organic acid secretory pathway. Since thiazides must gain access to the tubular lumen to inhibit the Na+-Cl- symporter, drugs such as probenecid can attenuate the diuretic response to thiazides by competing for transport into the proximal tubule. However, plasma protein binding varies considerably among thiazide diuretics, and this parameter determines the contribution that filtration makes to tubular delivery of a specific thiazide.


Thiazide diuretics rarely cause CNS (e.g., vertigo, headache, paresthesias, and weakness), GI (e.g., anorexia, nausea, vomiting, cramping, diarrhea, constipation, cholecystitis, and pancreatitis), hematological (e.g., blood dyscrasias), and dermatological (e.g., photosensitivity and rashes) disorders. The incidence of erectile dysfunction is greater with the Na+-Cl- symporter inhibitors than with several other antihypertensive agents (e.g., ¡3 receptor antagonists, Ca2+ channel blockers, angiotensin-converting enzyme inhibitors, and a1 antagonists) but usually is tolerable. Serious adverse effects of thiazides are related to abnormalities of fluid and electrolyte balance, including extracellular volume depletion, hypotension, hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, and hyperuricemia. Thiazide diuretics have caused fatal or near-fatal hyponatremia, and some patients are at recurrent risk of hyponatremia when rechallenged with thiazides.

Thiazide diuretics also decrease glucose tolerance, sometimes unmasking latent diabetes melli-tus. The mechanism of the impaired glucose tolerance appears to involve reduced insulin secretion and alterations in glucose metabolism; hyperglycemia is reduced when K+ is given along with the diuretic. In addition to contributing to hyperglycemia, thiazide-induced hypokalemia compromises the antihypertensive effect and cardiovascular protection afforded by thiazides in patients with hypertension. Thiazide diuretics may increase plasma levels of LDL cholesterol and triglycerides. The drugs are contraindicated in individuals who are hypersensitive to sulfonamides.

Thiazide diuretics may diminish the effects of anticoagulants, uricosuric agents used to treat gout, sulfonylureas, and insulin and increase the effects of anesthetics, diazoxide, cardiac glyco-sides, lithium, loop diuretics, and vitamin D. The effectiveness of thiazide diuretics may be reduced by NSAIDs and bile acid sequestrants (reduced absorption of thiazides). Amphotericin B and cor-ticosteroids increase the risk of hypokalemia induced by thiazide diuretics.

A potentially lethal drug interaction is that with antiarrhythmic drugs that prolong QT interval (ventricular repolarization) such as quinidine. Prolongation of the QT interval can lead to the development of polymorphic ventricular tachycardia (torsades de pointes) owing to triggered activity originating from early after-depolarizations (see Chapter 34). Although usually self-limiting, torsades de pointes may deteriorate into fatal ventricular fibrillation. Hypokalemia increases the risk of quinidine-induced torsades de pointes, and thiazide-induced K+ depletion may contribute to many cases of quinidine-induced torsades de pointes.

THERAPEUTIC USES Thiazide diuretics are used to treat edema associated with heart (congestive heart failure), liver (cirrhosis), and renal (nephrotic syndrome, chronic renal failure, and acute glomerulonephritis) disease. With the possible exceptions of metolazone and indapamide, most thiazide diuretics are ineffective when the GFR is <30-40 mL/min.

Thiazide diuretics decrease blood pressure in hypertensive patients and are used widely for the treatment of hypertension, either alone or in combination with other antihypertensive drugs (see Chapter 32). In this regard, thiazide diuretics are inexpensive, as efficacious as other classes of antihypertensive agents, and well tolerated. Thiazides can be administered once daily, do not require dose titration, and have few contraindications; moreover, they have additive or synergistic effects when combined with antihypertensive agents. Although thiazides may marginally increase the risk of sudden death and renal cell carcinoma, they generally are safe and reduce cardiovascular morbidity and mortality in hypertensive patients. Because adverse effects of thiazides

Inhibitors of Na+-Cl_ Symport (Thiazide and Thiazide-like Diuretics)

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