The hyperglycemic activity of benzothiadiazine and other diuretics

Life Sciences Yol . 4, pp . 1931-1936, 1965 . Printed in Great Britain.

Pergamon Press Ltd .

THE HYPERtILYCEMIC ACTIVITY OF BSNZOTHIADIAZINE AND OTHER DIURETICS I .I .A . Tabachalck,Arax Culbeakian and Ann Yaanell Department of Physiology and Biochemistry Schering Corporation, Bloomfield, N . J .

(Received 1 July 1965 ; in final form 18 August 1965) Considerable evidence is nvailable which demonstrates the tendency of certain benzothiadiazine diuretics to elevate blood glucose values in seemingly normal, as well as diabetic or pre diabetic, individuals (1-5) .

A recent review (5) concerning the

benzothiadiazine diuretics suggest that the hyperglycemic potential of all members of this chemical class is equivalent to their diuretic potency .

The paucity of data encouraged us to

determine systematically the degree of hyperglycemia elicited in rata by eleven benzothiadiazine diuretics . isoinfloline),

Chlorthalidoae (aa

quinethazone (a quinazoline), and ethacrnic acid

were included in this investigation as examples of diuretics of other chemical types . Methods Albino male rata, Charles River CD strain, weighing 175 to 225 gm ., were fed Purina lab chow ad libitum until the time of treatment . mg~kg .

All compounds were tested at two doses, 160 and 320

The drugs were solubilized using the minimum amount oY

alkali (1N NaOH), water at the same pH was administered to control rats .

The solutions were injected intraperitoneally in volumes

not exceeding 2 ml . per rat .

Blood was withdrawn from the dorsal

aorta of the rat, while under ether anesthesia, one hour after drug administration and plasma glucose levels were determined 1931

19 2

HYPERGLYCEMIC DIURETICS

Vol . 4, No . 20

using the Technicon Auto-Analyzer (modification of the ferricyavide method of Hoffman (7) .

This time period was chosen since

earlier work demonstrated that a single large dose of the antidiuretic s anti-hypertensive benzothiadlazine~ diazoxide would elicit hyperglycemia within one hour . The following diuretics were tested :

benzthiazide (Exna,

Robbins), hydroflumethazide (Saluron~ ßristol)~ chlorthiazide (Diuril~ Merck)

hydrochlorothiazide (Hydrodiuril, Merck)

cyclothiazide (Anhydron~ Lil.ly)~ polythiazide (Renese, Pfizer), bendroflumethiazide (Naturetin, Squibb), methylchlothiazide (Enduron, Abbott), quinethazone (Hydromox, Lederle), chlorthalidone (Hygroton, Geigy)~ trichlormethiazide (Naqua~ Schering), athacrynic acid (Merck), and diazoxide (Schering) . Results The experimental results are summarized in Table I .

At 160

mg~kg~ five of the benzothiadiazine diuretics (chlorothiazide, cyclothiazide~ polythiazide~ bendroflumethiazide~ and methyl chlothiazide) and the three non-benzothiadiazine diuretics (chlorthalidone, quinethazone~ and ethacrynic acid) elicited significant (p=0 .01) hyperglycemia .

The plasma glucose levels

were increased significantly (p=0 .01) by all diuretics at the 320 mg~kg dose s but comparison of the mean plasma glucose values at this dose revealed that trichlormethiazide was the least hyperglycemic agent tested .

No gross toxicity was noted in the rata

with any of the compounds tested at either dose .

In this table

are the mean glucose values observed in rats as a result of treatment with the anti-diuretic s anti-hypertensive benzothladiazine~ diazoxide (8) . Discussion There can be no question that hyperglycemia was produced in

HYPERGLYCEMIC DIURETICS

Yol . 4, No . 20

1933

TaBLE i Hyperglycemic Effects of Benzothiadiazines and Other Selected Diuretics Plasma Glucose Levels

m . 100 ml .*

Control

Treated 160 m . k .

Controls

Trichlormethiazide

165 (10)

172* *(10) ***

176 (45)

188

(45)

Chlorothiazide

165 (10)

~

(10)

172 (33)

201

(37)

Hydroflumethiazide

169

(5)

165

(5)

171 (37)

2~

(34)

Benzthiazide

169

(5)

169

(5)

172 (32)

22Q

(30)

Cyclothinzide

151 (10)

~

(10)

156 (10)

~

(8)

Polythiazide

129

(4)

1~1

(5)

151 (lo)

~L

(9)

Bendroflumethiazide

152

(5)

240

(8)

157 (10)

~0

(8)

DihydroChlorothiazide

l72

(5)

167

(5)

169 (23)

40~

(23)

Methyl Chlothiazide'

156

(5)

12~

(5)

149 (10)

~

(9)

Quinethazone

130

(4)

168 (22)

284

(22)

Chlorthalidone

130

(5)

(5)

174 (10)

~1Q

(9)

Diazoxide

187

(5)

422

(5)

l87

466

(5)

Ethacrynic acid

160

(5)

446

(5) .

Generic Name s)

~~ 154

(5)

(5)

Treated 20 m . k .

W i

*Means **Underlined values are significantly different (p=0 .01) from respective controls . ***Number oP rats per experiment .

Yol . 4, fto . 20

HYPEEGLYCEYIC DIURETICS

193

rats by the administration of 320 mg~kg of all the benzothiadiaziaes as well as chlorthalidone, quinethazone, and ethacrynic acid (160 mg~kg) .

It is evident that different degrees of hyper-

glycemia can be identified in the rat .

For example s trichlor-

methiazide, at 320 mg~kg, elicited a 7 percent increase in plasma glucose vhereas the same dose of methylchlothiazide caused a 264 percent increase in plasma glucose . Although it is possible to relate diuretic efficacy to structure (6) (the milligram potency of 2- or 3- substituted derivatives is greater than that of the non-substituted deriva tives and the same relationship is true for the hydrogenated thiazides), the relationship between structure and hyperglycemia in the rat is not as clear .

Trichlormethiazide, which elicits

minimal hyperglycemia in the rat (Table I), is one of the most potent diuretics tested, whereas other potent diuretics, such as cyclothiazide, polythiazide, bendroflumethiazide, and methylchlothiazide are very potent inducers of hyperglycemia in the rat .

Hydrochlorthiazide, at 320 mg~kg~ appears to be more hyper-

glycemic in the rat than hydroflumethiazide and benzthiazide are relatively weak hyperglycemic agents in the rat .

Hydrochlor-

thiazide, at j20 mg~kg, appears to be more hyperglycemic in the rat than hydroflumethiazide and benzthiazide (Table I), though all three diuretics are employed at equivalent maximum doses in man (5) . Conclusions The results of this study show that benzo~hiadiazine diuretics, other diuretics such as ethacrynic acid, quinethazone, sad chlorthalidone, and diazoxide, an anti-diuretic benzothiediazine elicit varying degrees o~f hyperglycemia .

There appeared

to be some correlation of the diuretic with hyperglycemic potency

Yol. 4, Ao . 20 of these drugs .

HYPERGLYCEIdIC DIIIBE'PICB

1935

However, some exceptions were noted .

Trichlor-

methiazide is unique in that this drug is one of the most potent diuretics tested, yet it appeared to induce only slightly elevated levels of plasma glucose .

Conversely, diazoxide, nn aati-

diuretic, is one of the moat potent hyperglycemic agents evaluatad in this study . The relationship between our findings in the rat sad clinical experience with diuretic-induced hyperglycemia is not clear . However, it may be inferred from our results that all drugs tested in this study would have some propensity to induce hyperglycemia in man, but the compound with the least likelihood to do so at clinical effective doses would be trichlormethiazide . Trichlormethiazide appears unique in that its potent diuretic action is not correlated with its low hyperglycemic potency, indicating that trichlormethiazide represents a drug with a potential separation between the two properties . REFERENCES 1.

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1936

FIYPEBGLYC~IC DIII&ETICS

Pol. 4, No . 20

7"

Hofiman, ~. S ., J . Hiol . Chem . 120 : 51, 1937 .

8.

Tabachnick, I . I . A ., Gulbenkian, A ., aad Seidman, F ., Diabetes 1~ :408, 1964 .