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Chapter: Basic & Clinical Pharmacology : Diuretic Agents

Nonedematous States

The diuretic and mild vasodilator actions of the thiazides are useful in treating virtually all patients with essential hypertension and may be sufficient in many.



The diuretic and mild vasodilator actions of the thiazides are useful in treating virtually all patients with essential hypertension and may be sufficient in many. Although hydrochlorothiazide is the most widely used diuretic for hypertension, chlorthalidone may be more effective because of its much longer half-life. Loop diuretics are usually reserved for patients with mild renal insufficiency (GFR 30–40 mL/min) or heart failure. Moderate restriction of dietary Na+ intake (60–100 mEq/d) has been shown to potentiate the effects of diuretics in essential hypertension and to lessen renal K+ wasting. A K+-sparing diuretic can be added to reduce K+ wasting.

There has been debate about whether thiazides should be used as the initial therapy in treatment of hypertension. Their relatively mild efficacy sometimes limits their use as monotherapy. However, a very large study of over 30,000 participants has shown that inexpensive diuretics like thiazides result in outcomes that are similar or superior to those found with ACE inhibitor or calcium channel-blocker therapy. This important result reinforces the importance of thiazide therapy in hypertension.

Although diuretics are often successful as monotherapy, they also play an important role in patients who require multiple drugs to control blood pressure. Diuretics enhance the efficacy of many agents, particularly ACE inhibitors. Patients being treated with powerful vasodilators such as hydralazine or minoxidil usually require simultaneous diuretics because the vasodilators cause sig-nificant salt and water retention.


Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. While there are numerous medical conditions (hyperparathyroidism, hypervitaminosis D, sarcoidosis, malignan-cies, etc) that cause hypercalciuria, many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the DCT and thus reduce the urinary Ca2+ concentration. Fluid intake should be increased, but salt intake must be reduced, since excess dietary NaCl will overwhelm the hypocalciuric effect of thi-azides. Dietary Ca2+ should not be restricted, as this can lead to negative total body Ca2+ balance. Calcium stones may also be caused by increased intestinal absorption of Ca2+, or they may be idiopathic. In these situations, thiazides are also effective but should be used as adjunctive therapy with other measures.


Hypercalcemia can be a medical emergency . Because loop diuretics reduce Ca2+ reabsorption significantly, they can be quite effective in promoting Ca2+ diuresis. However, loop diuretics alone can cause marked volume contraction. If this occurs, loop diuretics are ineffective (and potentially counterproductive) because Ca2+ reabsorption in the proximal tubule would be enhanced. Thus, saline must be administered simultaneously with loop diuretics if an effective Ca2+ diuresis is to be maintained. The usual approach is to infuse normal saline and furosemide (80–120 mg) intravenously. Once the diuresis begins, the rate of saline infusion can be matched with the urine flow rate to avoid volume depletion. Potassium chloride may be added to the saline infusion as needed.


Diabetes insipidus is due to either deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate respon-siveness to ADH (nephrogenic diabetes insipidus [NDI]). Administration of supplementary ADH or one of its analogs is effective only in central diabetes insipidus. Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes insipidus. Lithium, used in the treatment of manic-depressive disorder, is a common cause of NDI, and thiazide diuretics have been found to be very helpful in treating it. This seemingly paradoxic beneficial effect of thiazides was previously thought to be mediated through plasma volume reduction, with an associated fall in GFR, leading to enhanced proximal reabsorption of NaCl and water and decreased delivery of fluid to the downstream diluting segments. However, in the case of Li+-induced NDI, it is now known that HCTZ causes increased osmolality in the inner medulla (papilla) and a partial correction of the Li+-induced reduction in aquaporin-2 expression. HCTZ also leads to increased expression of Na+ transporters in the DCT and CCT segments of the nephron. Thus, the maximum volume of dilute urine that can be produced is significantly reduced in NDI. Dietary sodium restric-tion can potentiate the beneficial effects of thiazides on urine volume in this setting. Serum Li+ levels must be carefully moni-tored in these patients, because diuretics may reduce renal clear-ance of Li+ and raise plasma Li+ levels into the toxic range . Lithium-induced polyuria can also be partially reversed by amiloride, which blocks Li+ entry into collecting duct cells, much as it blocks Na+ entry. As mentioned above, thiazides are also beneficial in other forms of nephrogenic diabetes insipi-dus. It is not yet clear whether this is via the same mechanism that has been found in Li+-induced NDI.

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