These drugs contain the sulfonamide group -SO2NH2. They are suitable for oral administration. In addition to being filtered at the glomerulus, they are subject to tubular secretion. Their concentration in urine is higher than in blood. They act on the luminal membrane of the tubule cells. Loop diuretics have the highest efficacy. Thiazides are most frequently used. Their forerunners, the carbonic anhydrase inhibitors, are now restricted to special indications.
Carbonic anhydrase (CAH) inhibitors, such as acetazolamide and sulthi-ame, act predominantly in the proximal tubules. CAH catalyzes CO2 hydra-tion/dehydration reactions: H+ + HCO3- ^ H2CO3 ^ H2O + CO2.
The enzyme is used in tubule cells to generate H+, which is secreted into the tubular fluid in exchange for Na+. There, H+ captures HCO3-, leading to formation of CO2 via the unstable carbonic acid. Membrane-permeable CO2 is taken up into the tubule cell and used to regenerate H+ and HCO3-. When the enzyme is inhibited, these reactions are slowed, so that less Na+, HCO3- and water are reabsorbed from the fast-flowing tubular fluid. Loss of HCO3- leads to aci-dosis. The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the production of ocular aqueous humor. Present indications for drugs in this class include: acute glaucoma, acute mountain sickness, and epilepsy. Dorzolamide can be applied topically to the eye to lower intraocular pressure in glaucoma.
Loop diuretics include furosemide (frusemide), piretanide, and bumeta-nide. With oral administration, a strong diuresis occurs within 1 h but persists for only about 4 h. The effect is rapid, intense, and brief (high-ceiling diuresis). The site of action of these agents is the thick portion of the ascending limb of Henle's loop, where they inhibit Na+/K+/2Cl- cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excre-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
tion of Ca2+ and Mg2+ also increases. Special toxic effects include: (reversible) hearing loss, enhanced sensitivity to renotoxic agents. Indications: pulmonary edema (added advantage of i.v. injection in left ventricular failure: immediate dilation of venous capacitance vessels ^ preload reduction); refractoriness to thiazide diuretics, e.g., in renal hypovolemic failure with creatinine clearance reduction (<30 mL/min); prophylaxis of acute renal hypovolemic failure; hypercalcemia. Ethacrynic acid is classed in this group although it is not a sulfonamide.
Thiazide diuretics (benzothiadia-zines) include hydrochlorothiazide, benzthiazide, trichlormethiazide, and cyclothiazide. A long-acting analogue is chlorthalidone. These drugs affect the intermediate segment of the distal tubules, where they inhibit a Na+/Cl- co-transport. Thus, reabsorption of NaCl and water is inhibited. Renal excretion of Ca2+ decreases, that of Mg2+ increases. Indications are hypertension, cardiac failure, and mobilization of edema.
Unwanted effects of sulfonamide-type diuretics: (a) hypokalemia is a consequence of excessive K+ loss in the terminal segments of the distal tubules where increased amounts of Na+ are available for exchange with K+; (b) hy-perglycemia and glycosuria; (c) hyper-uricemia—increase in serum urate levels may precipitate gout in predisposed patients. Sulfonamide diuretics compete with urate for the tubular organic anion secretory system.
Anion secretory system
Anion secretory system
Uric acid yvvvvv*)*/
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