Late Distal Tubule And Collecting Duct

Blood Dyscrasias Chart

FIGURE 28-6 Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists. AIP, aldosterone-induced proteins; ALDO, aldosterone; MR, mineralocorticoid receptor; CH, ion channel; 1, activation of membrane-bound Na+ channels; 2, redistribution of Na+ channels from cytosol to membrane; 3, de novo synthesis of Na+ channels; 4, activation of membrane-bound Na+,K+-ATPase; 5, redistribution of Na+,K+-ATPase from cytosol to membrane; 6, de novo synthesis of Na+,K+-ATPase; 7, changes in permeability of tight junctions; 8, increased mitochondrial production of ATP. BL and LM indicate basolateral and luminal membranes, respectively.

FIGURE 28-6 Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists. AIP, aldosterone-induced proteins; ALDO, aldosterone; MR, mineralocorticoid receptor; CH, ion channel; 1, activation of membrane-bound Na+ channels; 2, redistribution of Na+ channels from cytosol to membrane; 3, de novo synthesis of Na+ channels; 4, activation of membrane-bound Na+,K+-ATPase; 5, redistribution of Na+,K+-ATPase from cytosol to membrane; 6, de novo synthesis of Na+,K+-ATPase; 7, changes in permeability of tight junctions; 8, increased mitochondrial production of ATP. BL and LM indicate basolateral and luminal membranes, respectively.

TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS

As with other K+-sparing diuretics, MR antagonists may cause Life-threatening hyperkalemia. Indeed, hyperkalemia is the principal risk of MR antagonists. Therefore, these drugs are con-traindicated in patients with hyperkalemia and in those at increased risk of developing hyperkalemia either because of disease or because of administration of other medications. MR antagonists also can induce metabolic acidosis in cirrhotic patients.

Salicylates may reduce the tubular secretion and decrease the diuretic efficacy of spironolactone, and spironolactone may alter the clearance of cardiac glycosides. Owing to its effects on other steroid receptors, spironolactone may cause gynecomastia, impotence, decreased libido, and menstrual irregularities. Spironolactone also may induce diarrhea, gastritis, gastric bleeding, and peptic ulcers (the drug is contraindicated in patients with peptic ulcers). CNS adverse effects include drowsiness, lethargy, ataxia, confusion, and headache. Spironolactone may cause rashes and, rarely, blood dyscrasias. Whether therapeutic doses of spironolactone can induce malignancies remains an open question. Strong inhibitors of CYP3A4 (see Chapter 3) may increase plasma levels of eplerenone; such drugs should not be administered to patients taking eplerenone, and vice versa. Other than hyperkalemia and GI disorders, the rate of adverse events for eplerenone is similar to that of placebo.

THERAPEUTIC USES Spironolactone often is coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. Such combinations result in increased mobilization of edema fluid with lesser perturbations of K+ homeostasis. Spironolactone is particularly useful in the treatment of primary hyperaldosteronism (due either to adrenal adenomas or bilateral adrenal hyperplasia) and refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites). Spironolactone is considered the diuretic of choice in patients with hepatic cirrhosis. Spironolactone, added to standard therapy, substantially reduces morbidity and mortality and ventricular arrhythmias in patients with heart failure (see Chapter 34).

Clinical experience with eplerenone is limited; it appears to be a safe and effective antihypertensive drug. In patients with acute myocardial infarction complicated by left ventricular systolic dysfunction, addition of eplerenone to optimal medical therapy significantly reduces morbidity and mortality.

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