Morton Fuchs

Some observations on the pharmacology of hydrochlorothiazide

T HE DISCOVERY of chlorothiazide has been a major development in diuretic therapy. It is as effective when given orally as when given by the parenteral route. The primary effect appears to be inhibition of renal tubular reabsorption of sodium and chloride resulting in a secondary increase in water excretion. There appears to be some carbonic anhydrase inhibitory effect on the renal tubules, particularly at larger d0ses.l In an attempt to improve the potency and decrease the incidence of certain side effects, a number of benzothiadiazine derivatives were synthesized by Novel10 and Sprague. The report includes our observations on the clinical pharmacology of hydrochlorothiazide (Hydrodiuril),t a compound which differs from chlorothiazide only in that the heterocyclic ring has been saturated by the addition of two hydrogen atoms (Fig 1).

Five Years' Experience with the Evaluation of Diuretic Agents

Twelve diuretics and 2 combinations of diuretics were evaluated by a standard methodology. Electrolyte excretion patterns were evaluated in “normal” hospitalized patients, and acute weight loss was evaluated in out-patients in congestive failure. The large standard errors of the means for natriuresis, kaluresis, and acute weight loss reflect the inherent biologic variation of such assays and permit separation of drugs into only a few overlapping categories of potency. The combination of a mercurial and a thiazide caused significantly greater sodium excretion than any other drug used alone. No single diuretic was significantly more potent than all others.

Treatment of edema by the combined administration of chemically different diuretic agents

Abstract Despite the fact that edema can generally be controlled with the use of a single potent diuretic agent, there is a small group of edematous patients in whom such therapy is not sufficient. Heretofore these latter patients have generally been treated with diuretic cocktails consisting of a parenteral mercurial in combination with one or more mild diuretic agents which serve primarily to potentiate the action of the mercurials. The present study indicates that the combined administration of various chemically different but individually potent (benzothiadiazine, phthalimidine and mercurial) diuretics has substantial additive diuretic actions. Use of the latter combinations is encouraged in patients with refractory edema.

Clinical experience with a new type of orally effective diuretic agent

Of the newer diuretic agents, many are modifications of a benzothiadiazine molecule. Although a ring system (sulfur‐1, 1‐dioxide) is found in all of these benzothiadiazine drugs, it has been found that this ring is not essential for saluretic activity. A new type of drug, a member of the quinazolinone sulfonamide family (quinethazone), has been found to be a saluretic agent of the same order of potency as hydrochlorothiazide with regard to its natriuretic activity. The sodium and potassium excretion ratio is high. The duration of activity appears to be approximately 24 hours. Administration of quinethazone for 2 days induced an average Weight loss of more than 2 pounds in a group of 30 outpatients. A study of the same patients who previously had required two or more mercurial injections a week indicated that daily administration of quinethazone maintained them in an edema‐free state without significant toxic effects.

Evaluation of flumethiazide (trifluoromethyl thiazide) in the outpatient clinic

Abstract 1. (1) An acute and chronic diuretic response study with flumethiazide has been described. 2. (2) Flumethiazide is an effective diuretic agent as determined by weight response in ambulatory cardiac patients. An effective dose appears to be 800 mg which is equivalent to the diuretic activity of 500 mg of chlorothiazide. 3. (3) Doses of flumethiazide greater than 2 Gm a day had no more effect on weight loss in the group of patients studied than did the 2 Gm dose. 4. (4) Chronic administration of 2 Gm a day of flumethiazide maintained a group of cardiac patients free of congestive failure complaints. There was no significant influence on serum electrolytes or on the blood count. 5. (5) Side effects were minimal and consisted primarily of pruritus in 3 out of 18 patients. The pruritus stopped when the drug was withdrawn.

Further observations on flumethiazide. A new oral diuretic agent.

Abstract 1. 1. Flumethiazide (Ademol) is an orally effective saluretic agent of the sulfamyl benzothiazide group of chemical compounds. 2. 2. The main effect of flumethiazide is on sodium, chloride and water excretion. Significant effects on potassium excretion were not observed. 3. 3. Renal hemodynamics did not seem to be altered when doses not exceeding 2,000 mg. were given. 4. 4. The maximum effect of continuous daily administration is reached within the first two days, and this is followed by gradual return of natruresis to the control level within four to six days.

Diuretic therapy in syndromes associated with sodium and water retention

Abstract In discussing some of the more common clinical syndromes of edema, we note that renal retention of sodium and water is a common denominator but that other factors such as decreased colloid osmotic pressure of the blood, decreased blood flow to the liver and decreased or abnormal hormonal activity may be the primary event and must be given primary therapeutic consideration. It is also seen that in varying degrees of importance, natriuretic (or diuretic) agents are a therapeutic common denominator for the treatment of symptoms associated with excessive sodium and water retention.

Diuretic effects of flumethiazide, a benzothiadiazine derivative.

Flumethiazide is a potent diuretic agent which may be safely administered to cardiac patients.Both short-term and long-term studies of a large group of patients with congestive heart-failure showed that flumethiazide produced no significant change in the glomerular filtration rate, renal plasma flow or blood pressure.Bio-assay studies revealed that flumethiazide produced a marked natruretic effect. With a therapeutic dose of from 200 to 2000 mg., the sodium excretion in response to flumethiazide was similar to that resulting from administration of chlorothiazide.

Diuretic Evaluation of Chlorazinal

The average weight loss after 48 hours in 14 ambulatory cardiac patients receiving chlorazinal was 1.6 lb., comparing favorably with the response to other oral diuretics. Determinations of blood urea nitrogen and creatinine levels and urinalyses in 29 patients receiving the drug indicated that it tends to increase blood urea and to increase cellular content and casts in the urine in certain patients; an exception was a patient with acute glomerulonephritis in whom the blood urea decreased.