HUMAN CLINICAL PHARMACOLOGY OF THE NEWER DIURETICS: BENZOTHIADIAZINE AND PHTHALIMIDINE

The introduction of chlorothiazide several years ago' stimulated active research in the benzothiadiazine group of diuretic agents. As a result of this research there has emerged a group of potent diuretics that have characteristics common to the thiazide group but there are pharmacological differences among these drugs that result from seemingly very minor changes in the basic benzothiadiazine structure. In FIGURE 1 the structural formula of the thiazide diuretics is shown. The changes that have been made in chlorothiazide, the parent compound, are a t the third, fourth, and sixth positions. The pharmacology of these diuretics can be divided into three groups at this stage of their development. The nonhydrogenated thiazides in clinical use today are chlorothiazide* (Diuril) and flumethiazidet (Ademol), FIGURE 1. These agents have an effective dose range of 200 mg. to 2000 mg. Doses greater than 2000 mg. give no greater saluretic or diuretic effects than the 2000 mg. dose itself. They have significant effects on the electrolyte excretion in the urine, with major iduence on the sodium, potassium, and chloride ions. The quantity of sodium and chloride excreted is approximately the same. Potassium excretion with chlorothiazide increases with dosage of the drug and is greatest a t the maximum doses, where the carbonic anhydrase inhibiting activity is most evident. With the substitution of the chloride atom by a trifluoromethyl group at the sixth position of chlorothiazide, which results in flumethiazide, there appears to be a change in the effect on potassium excretion. There is an increase in potassium excretion doses up to 400 mg. but, unlike chlorothiazide, larger doses do not appear to have any greater influence? Hydrogenated thiazides. By the addition of two hydrogen atoms at the third and fourth positions of the basic structure the hydrogenated group of thiazides is produced. The hydrogenation of chlorothiazide results in hydrochlorothiazideS (Hydrodiuril, Esidrix, Oretic), and the addition of the hydrogen atoms to the third and fourth positions of flumethiazide results in hydroflumethiazides (Saluron), FIGURE 1. The hydrogenation of these compounds reduces their dose range to 25 to 200 mg., and doses greater than 200 mg. have no greater effect on sodium excretion. Thus a dosage ratio of 1O:l exists between the nonhydrogenated and hydrogenated drugs mentioned.8 Another pharmacological characteristic of hydrogenation is the change in the electrolyte excretion pattern. The Nonhydrogmted thiazide.