Benzothiadiazine (thiazide) diuretics

Progress Notes in Cardiology Edited

by EMANUEL GOLDBERGER,

New York,

M.D.,

New York

Benzothiadiazine

W

F..~.c.c.

(Thiazide)

the past year a variety of new diuretics have become available for the treatment of all forms of edema and hypertension. Those compounds of the benzothiadiazine structure now commercially available are Structural formulas of these listed in Table I. compounds are given in Figure 1. All are potent diuretic agents, producing, in the usual dose range, a marked increase in urinary volume and sodium chloride excretion, and a lesser increase in potassium and bicarbonate excretion. Their electrolyte excretion patterns resemble that of a mercurial diuretic more closely than that of a carbonic anhydrase inhibitor. In contrast to this latter group of diuretics, the benzothiadiazines usually retain their effectiveness on long term therapy. Diuretic Effect: In all types of edema, including edema produced by cardiac, renal and hepatic disease, drugs such as cortisone, toxemia of and premenstrual edema, these pregnancy “thiazides” are potent, rapid acting and of a Although they- act very low degree of toxicity. in vitro as carbonic anhydrase inhibitors, their main action in man and animals seems to be due to decreased renal tubular reabsorption by a mechanism or at a location different from that of Studies of renal function show the mercurials. no significant change in glomerular filtration rate or renal plasma flow with these diuretics. The benzothiadiazine Hypotensive Action: diuretics reduce high but not normal blood pressures and potentiate the antihypertensive action of the rauwolfia and veratrum alkaloids, the ganglionic blocking agents hydralazine, (including the latest one, trimethidinium methosulfate) and the newest antihypertensive agents, The dose guanethidine and bretylium tosylate. of ganglionic blocking agents should be reduced by half when a “thiazide” saluretic is added to The effective dose of these agents the regimen.

Diuretics

in patients who have had a sympathectomy be as little as one-tenth the usual dose.

ITHIN

may

Side Efects and Electrolyte Disturbances: The side effects of thiazide diuretics are usually minimal but include nausea, anorexia, skin rashes and other allergic manifestations. More important is the possibility of electrolyte abnormalities such as hyponatremia, hypochloremia, hyperuricemia, metabolic alkalosis and hypokalemia. Except for the latter, these abnormalities are usually transient and asymptomatic. Administration of chlorothiazide has apparently precipitated clinical gout although the elevated serum uric acid produced usually causes no No clinical cases of gout have been symptoms. reported for the flumethiazide series; administration of jhunethiazide and hydroflumethiazide produces only a small initial increase in serum uric acid which returns toward normal Patients who have had on continued therapy. gout while receiving chlorothiazide have continued on flumethiazide without recurrence

TABLE Commercially

Available

I

Benzothiadiazine Diuretics

(Thiazide)

I Generic

Name

Trade Name(s)

hianufacturer

Range of Usual Daily Dose (mg.)

I

428

’_____

Chlorothiazide

Diurils

Flumethiazide

.4demol@

Hydrochlorothiazide

Hydro Diuril Esidrix’a Oretic

Merck Ciba Abbott

25-200 25-200 25-200

Hydroflumethiazide

Di-Ademila Saluron

Squibb Bristol

25~200 25-200

Benzydroflumethiazide

Naturetin

Squibb

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FLUMETHIAZIDE

Notes

HYDROFLUMETHIAZIDE

CHLOROTHIAZIDE rrc

1. Structural

formulas

of symptoms. Thrombocytopenic purpura has occurred in patients receiving chlorothiazide but not in patients receiving other thiazides. This may be a matter of insufficient clinical experience with the newer drugs rather than a real difference. Allergic reactions to administration of chlorothiazide or hydrochlorothiazide have disappeared when the patients were transferred to flumethiazide or hydroflumethiazide with continuation of equivalent diuretic Hyperglycemia or antihypertensive actions. and glycosuria may also develop. Hypokalemia: The most serious side effect of these diuretics is hypokalemia which occurs in as many as 40 per cent of patients receiving chlorothiazide or hydrochlorothiazide without supplementary potassium. Although clinical signs are not noted in many patients with a chemical hypokalemia, lassitude, lethargy, muscle weakness and cardiac arrhythmias, frequently associated with digitalis intoxication, Complete muscular paralydo occur regularly. sis accompanied by hypokalemia has been reported in a patient receiving chlorothiazide. For this reason patients receiving these drugs should supplement their normal dietary intake with 1 to 6 gm. daily of potassium chloride or However, hypokalemia due to adcitrate. ministration of chlorothiazide or hydrochlorothiazide is not always corrected by the usual doses of supplementary potassium salts. Comparison of Various Thiazide Derivatives: Replacement of the chlorine group of chlorothiazide and hydrochlorothiazide with the trifluoromethyl group of flumethiazide and hydroflumethiazide appears to result in decreased potassium bicarbonate excretion at doses producing equivalent losses of sodium chloride and water. Thus, in one study ten patients under MARCH

1960

429

in Cardiology

BENZYDROFLUMETIIIAZIDE

HYDROCHLOROTHIAZIDE of benzothiadiazine

compounds.

controlled metabolic conditions were each given alternately 1 gm. of flumethiazide and 1 gm. of chlorothiazide with a five- to seven-day interval between to permit a return to control status. No significant differences were observed between the two drugs in their effect on the amounts of sodium, chloride and urine excreted in the twenty-four hours after the drug was given. However, the average excretion of potassium in the twenty-four hours after administration of flumethiazide was 9 mEq. as compared with an excretion of 17 mEq. for the same period after 1 gm. of chlorothiazide was given. The corresponding values for bicarbonate were 6 mEq. with flumethiazide and 15 mEq. with chlorothiazide. Administration of flumethiazide caused an increase in pH of only 0.5 over the control level (pH 5.2 increased to 5.7) whereas administration of chlorothiazide caused an increase of 2 (pH 5.2 increased to pH 7.2). Animal and human pharmacology and clinical experience indicate that at doses producing the same loss of sodium chloride and water, benzydroflumethiazide produces less potassium bicarbonate loss than the other diuretics of this type. The addition of two hydrogen atoms to the chlorothiazide or flumethiazide molecule to form the corresponding “hydra” derivative increases the potency somewhat more than tenThus, a 50 mg. tablet of hydrochlorothiafold. zide appears to be somewhat more effective as a saluretic, diuretic and antihypertensive agent than a 500 mg. tablet of chlorothiazide. Howand flumethiazide ever, these two diuretics, and probably hydroflumethiazide as well, have the same natriuretic effect when compared at their optimal doses or the same fraction thereof. They are also probably equally as effective di-

430

Progress

Notes

uretics or antihypertensive agents in most patients when given at their optimal doses. However, there is apparently some specificity in the reaction of different patients to the drugs Those few patients who do not in this group. respond well to chlorothiazide initially or after months of therapy may- respond satisfactorily to hydrochlorothiazide or one of the flumethiazide series. Chloruresis is less than natriuresis with chlorothiazide and flumethiazide but exceeds sodium excretion following hydrochlorothiazide or hydroflumethiazide administration. Potassium excretion does not rise proportionately with sodium and chloride excretion as dose is increased, particularly with flumethiazide and hydroflumethiazide. Clinical Studies in Heart Failure and HJ$ertension: Recent clinical studies on benzydrotlumethiazide have been made by Dr. Ralph V. Ford, Houston, Texas, in the treatment of edema, and by Dr. Burton M. Cohen, Elizabeth, New Jersey, They studied in the treatment of hypertension. separate groups of five or more patients under standardized metabolic ward conditions and found that 5 mg. of benzydroflumethiazide induced much greater increases in water, sodium and chloride excretion, but smaller increases in potassium and bicarbonate excretion than did 1 gm. of chlorothiazide. Five mg. of benzydroflumethiazide also induced greater increases in water loss and smaller increases in potassium and bicarbonate excretion than did 50 mg. of hydrochlorothiazide, but about the same increase in the excretion of sodium and chloride. Increases in urinary pH averaged 2 for this dose of chlorothiazide, 0.8 for the hydrochlorothiazide, and 0.2 for the benzydroflumethiazide. The average weight loss in twenty-four hours for similar separate groups of ten cardiac patients each following administration of 1,000 mg. of chlorothiazide was 0.7 lb., after 50 mg. hydrochlorothiazide 0.9 lb. and after 5 mg.

in Cardiology benzydroflumethiazide 1.4 lb. Treatment of twenty patients having edema due to cardiac, cirrhotic, or nephrotic conditions, steroids, or pregnancy with 10 mg. benzydroflumethiazide daily for twenty-one days resulted in good weight Ioss without significant change in serum sodium, potassium, carbon dioxide combining power, blood urea nitrogen or hematocrit. Benzydroflumethiazide in daily doses of 12.5 to 20 mg. daily reduced the average blood pressure of twenty previously untreated hypertensive patients with Smithwick grades 2 to 4 from 184/115 to 156/95 mm. Hg. When benzydroflumethiazide was substituted for chlorothiazide in one-hundredth thedose, theaverage blood pressure of a group of five patients decreased from 164/104 to 156/95 mm. Hg. Substitution of one-tenth the dose of benzydroflumethiazide for hydrochlorothiazide or hydroflumethiazide resulted in further decreases in blood pressure averaging 170/l 11 to 159/96 mm. Hg and 152/99 to 145/92 mm. Hg, respectively. Of the thirty-nine patients in these groups receiving benzydroflumethiazide as the sole treatment for hypertension, twenty-eight remained entirely free of untoward effects throughout the period of treatment. Among the remaining patients, untoward occurrences had the following incidence: cramps in the leg, four; abdominal cramps, two; diarrhea, three; nausea, three; paresthesia, one; pruritus, two; and skin rash, one. The data summarized in the previous two paragraphs illustrate the results obtained with benzydroflumethiazide in more than 1,000 patients with edema and hypertension in Europe This new diuretic is the most and America. It appears to be safer, partly potent available. because of its decreased effect on potassium excretion, and perhaps, because it is also more effective than other diuretics of this type. Further studies are awaited with interest.

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