Chlorothiazide

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In 1943 Sharp & Dohme Inc. (merged with Merck and Company in 1952 to become Merck, Sharp and Dohme (MSD)) had set up what came to be known as the Renal Program headed by Karl H. Beyer, a pharmacologist, and James M. Sprague, an organic chemist (Fig. 6). Prompted by the work of Roblin on heterocyclic sulfonamides, the renal team embarked on an exploration of other sulfonamide derivatives that could mobilize edema by the elimination of sodium with chloride, rather than bicarbonate. Starting with sulfanilamide and modifying its structure, a series of compounds were developed and studied for their natriuretic and chloruretic properties. The first drug, dirnate, while a diuretic in animals, had limited success clinically. In 1955, 6V2 years after the report by Schwartz, Frederick C. Novello, an organic chemist recruited to the Renal Program, synthesized chlorothiazide, and another pharmacologist who had joined the Renal Program, John E. Baer, showed that the new compound increased the excretion of sodium and chloride in almost equal amounts with minimal loss of bicarbonate. This was a landmark discovery that was to revo-

Karl Beyer Thiazide Diuretics

FIGURE 6. The Renal Team at Merck, Sharp & Dohme Research Laboratories responsible for the discovery and development of chlorothiazide, which was recognized by the Lasker Award in 1975. From left to right: John E. Baer, Ph.D.; Karl H. Beyer, Jr., M.D., Ph.D.; Frederick C. Novello, Ph.D.; and James M. Sprague, Ph.D. (c. 1966).

FIGURE 6. The Renal Team at Merck, Sharp & Dohme Research Laboratories responsible for the discovery and development of chlorothiazide, which was recognized by the Lasker Award in 1975. From left to right: John E. Baer, Ph.D.; Karl H. Beyer, Jr., M.D., Ph.D.; Frederick C. Novello, Ph.D.; and James M. Sprague, Ph.D. (c. 1966).

lutionize the treatment of edema. Fourteen months of clinical tests established chlorothiazide as a safe orally effective diuretic that began to be marketed in 1957 [4, 5]. Initially, chlorothiazides were thought to act in the ascending loop of Henle. Subsequent studies, however, identified its principal site of action on the distal tubule, with a small acetazolamide-like effect in the proximal nephron.

Two of the first clinical reports on chlorothiazide, published in 1957, were on its use in the treatment of hypertension. Edward Freis and Use Wilson in Washington and William Hollander and Robert Wilkins in Boston independently reported the effectiveness of chlorothiazide in the treatment of hypertension [9]. While a role for salt restriction in the treatment of hypertension had been used and the Kempner Diet, then in style, had its strong advocates, the use of a diuretic agent in the management of hypertension had not been entertained seriously.

Because of their safety and effectiveness as oral agents in the management of edema and hypertension, as well as their usefulness in the exploration of renal function in the laboratory, the sulfonamyl diuretics can easily be ranked among the most important pharmacological discoveries and, alongside the antibiotics, one of the noteworthy drugs of post-World War II medicine.

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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