Clinical evaluation of chlorothiazide.

CHLOROTHIAZIDE, commercially available as Diuril, was introduced to the general medical profession January 1, 1958. It had been available to clinical investigators during the previous year. In this span it has won wide acceptance as an oral diuretic and antihypertensive agent. These comments should be considered in the light of this relatively brief experience. The chemical structure of chlorothiazide is shown in figure 1. Chlorothiazide, acetazola-mide, and sulfanilamide all have the sulfamyl group. As a result of this structural similarity , chlorothiazide, like sulfanilamide and acetazolamide, is an inhibitor of the enzyme, carbonic anhydrase. However, the ability of chlorothiazide to inhibit carbonic anhydrase plays only a small role in the drug's long-term action.1 Chlorothiazide is rapidly absorbed from the gastrointestinal tract and is well tolerated intravenously.2 It is rapidly excreted by the kidneys, both by glomerular filtration and by tubular excretion. Approximately 30 to 50 per cent of the oral dose is excreted in 24 hours and over 90 per cent of the intravenous dose in 6 hours. Following oral ingestion, the drug is active for 6 to 12 hours and after intravenous administration for 2 to 4 hours. DIURETIC ACTION The most noteworthy action of chlorothia-zide is its ability to increase the urinary ex-cretion of sodium, potassium, chloride, and water.3 This increase may occur immediately after intravenous injection (table 1). The initial excretion of these electrolytes is accompanied by the diuresis of bicarbonate. After 24 hours bicarbonate excretion falls and the principal electrolytes excreted are sodium, potassium, and chloride. Figure 2 shows the effect of chlorothiazide on the ex-cretion of water and electrolytes and on the composition of the blood. Immediately after the administration of 1 Gm. of chlorothiazide there was prompt weight loss, increased urinary output, a large increase in sodium, potassium, and chloride excretion. On the first day, bicarbonate excretion was elevated and the pH of the urine relatively alkaline. By the ninth day of therapy there was still a brisk diuresis of water, sodium, and chloride but little increase of potassium excretion over control levels. Bicarbonate excretion was much lower. There was a relatively constant serum sodium level, a slight fall in serum potassium, and no change in serum chlorides during this period. Carbon dioxide content of the serum had increased 3 mEq./I. during the study. During the posttreatment period, there was a prompt increase in body weight, a sharp retention of sodium and chloride, and …