The antihypertensive activity of diuretics was discovered in the clinic. Diuretics do not lower arterial pressure in acute experiments on normotensive animals. Only in chronic experiments on DSS or SH rats can the mild antihypertensive effect of diuretics be detected. The first diuretic found to lower arterial pressure in hypertensive patients was chlorothiazide, discovered by Beyer and his colleagues at Merck. Its discovery was soon followed by the introduction of hydrochlorothiazide, a closely related derivative with much higher relative potency that was discovered at Merck as well as at Ciba-Geigy. Many similar thiazides have been subsequently developed and marketed, but only a few are still available on the American market. The major side effect of thiazides is hypokalemia, due to the excessive excretion of K+ ions. Other side effects include hyperuricemia and hyperglycemia. The search for diuretics with longer duration of action and fewer side effects led to the discovery of 'thiazide-like' diuretics, including metalozone, chlorthalidone, and indapamide (Table 1), which are chemically different from, but pharmacologically similar to, thiazides. Metolazone may produce diuresis in patients with a low glomerular filtration rate (below 20 mLmin _ 1), while thiazides tend to lose their effectiveness in such patients. Since the maximal obtainable saluretic effect of thiazides is low, diuretics with a higher ceiling effect - furosemide, bumetanide, torasemide and ethacrynic acid (Table 1) - have been introduced. These so-called loop diuretics have a much steeper saluretic dose-response curve than thiazides or 'thiazide-like' diuretics. Their antihypertensive effect is, however, not more pronounced or sustained than that of thiazides. Since water and/or electrolyte depletion is more likely to be produced by loop diuretics than by thiazides or thiazide-like diuretics, their use in the treatment of hypertension should be limited to patients who fail to respond to thiazides or patients with heart failure and/or severe edema who can benefit from the rapid salt depletion. The mechanism of action of diuretics within renal tubules is reasonably well understood. Thiazides and thiazide-like diuretics inhibit the Na+ -Cl_ symport in the distal convoluted tubules, blocking the reabsorption of these ions at the luminal site of
Table 1 Commonly used diuretics
Usual daily dose (mg) Oral bioavailability (%>) t1j2 (h)
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