A 50-year-old female has been receiving a diuretic for the treatment of essential hypertension. This drug acts by increasing the calcium content of urine and is the drug of choice for reducing acute pulmonary edema in congestive heart failure. Its side effects include ototoxicity and hyperuricemia. What is the most likely mechanism of action of this drug?
Correct Answer: B
B: Loop diuretics inhibit the Na/K/2Cl cotransporter of the luminal membrane in the ascending limb of the loop of Henle. Therefore, reabsorption of Na, K, and CL is decreased. The loop diuretics are the most efficacious of the diuretic drugs because the ascending limb accounts for the reabsorption of 25-30 % of filtered NaCl and downstream sites are not able to compensate for this increased Na load. Loop diuretics are the drugs of choice for reducing acute pulmonary edema in congestive heart failure. Loop diuretics act promptly, even among patients who have poor function or who have not responded to thiazides or other diuretics. Adverse side effects include ototoxicity, particularly when used in conjunction with the aminoglycoside antibiotics. Furosemide and ethacrynic acid compete with uric acid for the renal and biliary secretary system, thus blocking its secretion, and thereby causing or exacerbating gouty attacks. A: Aldosterone receptor antagonist is incorrect.
Spironolactone is a synthetic aldosterone antagonist that competes with aldosterone for intracellular cytoplasmic receptor sites. Because spironolactone chemically resembles some of the sex steroids, it does have minimal hormonal activity and may induce gynecomastia in males and menstrual irregularities in females.
C: Inhibition of carbonic anhydrase is incorrect. Acetazolamide inhibits carbonic anhydrase, which is located intracellulary and on the apical membrane of the proximal tubular epithelium. The decreased ability to exchange NA for H in the presence of acetazolamide results in a mild diuresis. The adverse side effects of acetazolamide include metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and paresthesia. D: Acts as osmotic diuretic is incorrect. A number of simple, hydrophilic, chemical substances that are filtered through the glomerulus, such as mannitol and urea, result in some degree of diuresis. This is due to their ability to carry water with them into tubular fluid. Osmotic diuretics are a mainstay of treatment for patients with increased intracranial pressure or acute renal failure due to shock, drug toxicities, or trauma. E: Blocking of the NaCl cotransporter is incorrect. The thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of Na by inhibition of an Na/Cl cotransporter on the luminal membrane. As a result, these drugs increase the concentration of NA and CL in the tubular fluid. Hypokalemia is the most frequent problem encountered with the thiazide diuretics and can predispose patients on digitalis to ventricular arrhythmias.
Thiazides increase serum uric acid by decreasing the amount of acid excreted by the organic acid secretory system. The thiazides inhibit the secretion of calcium, sometimes leading to elevated levels of Ca in the blood.
