Reprinted from NEW YORK STATE JOURNAL OF MEDICINE. Vol. 68, No. 1. Jan. 15. 1968 Copyright 1968 by the Medical Society of the State of New York and reprinted by permission of the copyright owner. Antihypertensive Action of Benzothiadiazines EDWARD D. FREIS, M.D. Washington, D.C. Senior Medical Investigator, Veterans Administration Hospital C HLOROTHIAZIDE and other diuretics of similar structure have become established as valuable therapeutic agents in the con- trol of hypertension. While not entirely free of toxicity, these drugs produce few disturbing side-effects. In addition, they have a relatively flat dose response curve in the therapeutic range. This permits fairly uniform dose schedules, which is an important feature of drugs used in general practice. Finally, they have the valuable characteristic of enhancing the antihyper- Presented at the Third International Pharmacologic Con- gress under the auspices of the International Union of Pharmacology, Sao Paula, Brazil, July 24 to 30, 1966. tensive effects of other blood pressure-re- ducing drugs such as reserpine, hydralazine, guanethidine, and methyldopa. This per- mits lower and, hence, less toxic doses of the latter drugs. Mechanism of antihypertensive effect Three possible mechanisms have been advanced to explain the antihypertensive effects of the thiazide diuretics. The first two implicate the sodium-depleting effect of chlorothiazide while the third claims that thiazides act by a vasodilator mechanism that is independent of the saluretic effect. A specific vasodilator effect of chloro- thiazide discrete from its natriuretic action was first proposed by Hollander, Chobanian, and Wilkins. l Their evidence was based on the observation that normotensive control subjects did not exhibit an anti- hypertensive effect, despite a similar diure- sis, and that the reduction in blood pressure began prior to a significant diuresis. This view received some support by the later discovery of diazoxide, a chemically re- lated benzothiadiazine compound. The January 15, 1968 / New York State Journal of Medicine 259 latter agent reduces blood pressure and at the same time induces sodium retention. Q -a Further analysis of the hemodynamic effects of diazoxide indicate, however, that its mode of antihypertensive effect is quite different from the diuretic benzothiadiazine compounds. The antihypertensive effect occurs immediately following intravenous injection and is rather transient in con- trast to the diuretic compounds which re- quire a longer period to act and then exert a more prolonged antihypertensive effect. Diazoxide appears to be a vasodilator com- pound since the hypotensive response is associated with an increase in cardiac output and a considerable decrease in total peripheral resistance similar to the action of peripheral vasodilators such as amyl nitrite or nitroprusside. *e4 The acute antihypertensive effect of chlo- rothiazide on the other hand is associated with a decrease in cardiac output, while total peripheral resistance usually increases.s-7 It thus appears that d&oxide has an immediate vasodilator action which seems to be minimal or absent in chlorothiazide. The argument that chlorothiazide re- duces blood pressure prior to a significant saluresis has been disputed by other observ- ers who found that the reduction of arterial pressure occurred only during and after the period of maximum salt 10ss.*-~Q Most investigators now agree that the antihypertensive effects of thiazides are related to their ability to produce a sodium diuresis. In fact all drugs which can produce a similar degree of sodium loss will exert a comparable antihypertensive effect such as parenteral mercurialsl and ethacry- nit acid." It is also well known that diets rigidly restricted in sodium will lower blood pressure and will enhance the antihyper- tensive effects of blood pressure-reducing drugs as well as surgical sympathectomy. 12 However, the manner in which sodium depletion reduces arterial pressure is still in dispute. There is considerable evidence that the reduction in plasma and extracellular fluid volume which accompanies the diure- sis is the important factor in bringing about the initial reduction of blood pres- sme.Q.l3-17 In nonedematous subjects, the diuresis brings about a loss of approxi- mately 2 L. of extracellular fluid volume of which 300 to 400 ml. represent plasma volume. 17* The antihypertensive effects of thiazides can be reversed in many patients by re- expanding the plasma volume with salt- free dextran solutionQ,Q.16*18 or by adminis- tering sufficient salt, 15 to 25 Gm. orally per day, to cause a return to control body weight.13.15 Depletion of blood volume by even small amounts will enhance the antibypertensive effects of certain agents, particularly of drugs which interfere with sympathetic vasoconstrictor responses. lg This does not explain, however, how depletion of blood volume by such a relatively small amount could reduce blood pressure in hypertensive patients who are not also receiving other antihypertensive drugs.20 It is of interest that thiazides do not reduce blood pressure in young normotensive subjects eventhough they produce a comparable diuresis and depletion of plasma volume. l3 The reduction of arterial pressure in- duced by chlorothiazide in hypertensive patients while significant is not of great magnitude. 2o To explain it on the basis of plasma volume depletion, several mech- anisms may be considered. The first in- volves the observation that the pressor response to infused norepinephrine in normal subjects is sign%cantly reduced following diuresis with chlorothiazide or mercurial agents.21~22 After restoration of plasma volume with salt-free dextran, the blood pressure responsiveness of these normal subjects returned toward and in some cases completely to normal. If the fall in plasma volume (and possibly tissue pressure) diminishes reactivity to any pressor stimulus, then chlorothiazide would also diminish the response to the unknown pressor mechanism which produces essential hypertension. Thus, thiazides reduce blood pressure when an abnormal hyper- tensive stimulus is in operation. Pressor responses of all types are dampened or diminished. A second explanation for the moderate depressor effect of relatively small decre- ments in plasma and extracellular fluid volumes in hypertensive patients involves the baroreceptor mechanism. With aging and hypertension, homeostatic adjustments to either depressor or pressor stimuli tend to become less brisk and effective.Q3e24 Mod- 260 New York State Journal of Medicine / January 15, 1968 erate decreases in plasma and extracellular fluid volumes are not completely balanced by compensatory vasoconstriction as oc- curs in young normal subjects. It is pertinent in this regard that elderly normotensive subjects also show some re- duction of arterial pressure following thia- zide-induced diuresis. 2L Such faulty buf- fering of blood pressure may be due to reduced compliance of the aorta and carotid artery which occurs with aging and hyper- tension since the baroreceptor nerves are stimulated by stretching of the arterial wall. Thus, three possible mechanisms have been invoked to support the "volume" theory of blood pressure reduction pro- duced by thiazides, as follows: (1) enhance- ment of depressor agents or stimuli, (2) damping of pressor stimuli resulting from plasma volume reduction, and (3) reduced baroreceptor responsiveness of hyperten- sive patients to such volume depletion. The third explanation that has been advanced to explain the antihypertensive effects of thiazides also involves sodium loss. However, in this case the loss of sodium is said to reduce arteriolar con- striction either by "dehydrating" the arteriolar walls or by affecting the con- centration gradient of extracellular to intracellular sodium. The latter theory was advanced by Friedman, Nakashima, and Friedman. 26 Tobian et al.,2' however, could find no change in the electrolyte composition of small arterial walls nor of their water content after chlorothiazide. No changes in the electrolyte concentration of the tissues could be found by other in- vestigators either in intact28 or nephrecto- mized28 animals following this drug. This is not surprising since the early studies in man indicated the excreted sodium was derived from extracellular fluid and that water and sodium chloride were lost from that space in isotonic proportion.17a Thus, although these theories are attractive in their simplicity there is little objective evidence to support them. There has been much discussion con- cerning the difference between the long- term and the short-term effects of thiazides. Whereas, Conway and Lauwerssl found plasma and extracellular fluid volume depletion in the first week of treatment with chlorothiazide, these were found to return to normal after one month of treatment despite continued reduction of blood pres- sure. They also found cardiac output re- duced after one week but normal after one or more months of continued treatment. For these reasons, they postulated that the thiazides act by some mechanism other than volume depletion during long-term therapy. Since body weight was reduced in their patients despite return to normal of the extracellular fluid volume, they postulated that there was a reduction in intracellular fluid volume during long-term treatment which might play a part in the continued reduction of blood pressure. Wilson and Freisu: also found a return of plasma and extracellular fluid volumes toward but not entirely back to control levels. Body weight returned in equal proportion to extracellular fluid in contrast to the observations of Conway and Lau- wers.sl On withdrawal of chlorothiazide after four to eight months of treatment Wilson and Freisl7: observed an overshoot of body weight, extracellular fluid, and plasma volumes to above control values. Blood pressure, however, did not rise entirely to control. It is apparent from studies of the long- term hemodynamic effects of other anti- hypertensive agents that considerable mod- ification of the initial drug action takes place with time, even though the blood pressure remains reduced. Thus, the re- duction of cardiac output found in the initial period of guanethidine treatment disappears with continued treatment, and the hypotension is now due to a reduced total peripheral resistance.32 Hydralazine initially increases cardiac output which later returns to normal during long-term therapy. 33 Similarly, the abnormalities in plasma volume and extracellular fluid space become modified after long-term treatment with chlorothiazide, but they are not entirely reversed even at six months ac- cording to the chronic studies carried out by Wilson and Freis.`Ta Strong evidence that the drug's basic action has not changed is provided by the prompt increase in these tluid compartments when chlorothiazide was discontinued. Instead of searching for an alteration in fundamental drug action with time, it may be preferable to attempt to clarify the nature of the change in the hypertensive process which produces the return to nor- January 15, 1968 / New York State Journal of Medicine 261 ma1 hemodynamic conditions regardless of the type of agent used. Toxic effects of benzothiadiazines Hypokalemia is the most frequent side- effect produced by thiazide treatment. Despite initial concern about potassium deficiency, there has been no clinical evidence of renal damage or other serious manifestations of depletion of body potas- sium even in patients treated continuously for over five years with thiazides. Total exchangeable potassium remains unaltered during long-term treatment in man34835 or animals.36 Thus, despite an initial moder- ate kaluresis, both clinical and experimental evidence suggests that the hypokalemia probably represents a disturbance in the potassium gradient between the extracellu- lar fluid and tissue cells rather than a serious depletion of the body's stores of potassium. l3 Clinically, the hypokalemia has little significance except in the poten- tiation of digitalis toxicity. The mechanism of the reduced serum potassium is not clear. The principal site of action of the drug appears to be at the proximal renal tubules, whereas po- tassium excretion occurs primarily in the distal tubules. The salt loss is said to stim- ulate the production of renin, which would, in turn, increase aldosterone pro- duction with possible kaluretic effects.37 Moderate elevation of carbon dioxide- combining power can occur with thiazide administration, and metabolic alkalosis can cause a migration of potassium ions into cells. Another common side-effect is hyperuri- cemia as was first pointed out by Laragh, Heinemann, and Demartini.38 They found that while large parenteral doses were uricosuric, the customary oral doses blocked the renal tubular transport mechanisms for urate. 39 It is apparent clinically that gout is aggravated by benzothiadiazines and possibly may be caused by the drug. The hyperuricemic effect of the thiazides is readily overcome by probenecid or by allopurinol, the latter drug being especially effective in this regard.40 The development of hyperglycemia in occasional patients receiving thiazide drugs was first pointed out by Finnerty.41 Carbohydrate tolerance tests carried out by Shapiro, Benedek, and Sma1142 in thiazide-treated elderly hypertensive sub- jects indicated that further impairment of carbohydrate metabolism occurred in "po- tential diabetics" as judged by family history and prior glucose tolerance tests but not in "nondiabetic controls." No change in insulin requirement was found in a series of female diabetic patients who received chlorothiazide throughout the course of pregnancy.43 These patients received supplemental potassium and also did not exhibit hypokalemia while under treatment. Others have found increases in blood sugar, especially postprandial blood sugar. 44 -46 Although Wolff et al.44 believed that permanent diabetes may be produced by thiazides in nondiabetic pa- tients, others have found that the hyper- glycemia is reversible on stopping the drug. 45.46 In the Veterans Administration Cooperative Study on Antihypertensive Agents the incidence of diabetes was no higher in the group receiving chlorothiazide than in patients treated by other means.47 The burden of evidence indicates that while thiazides may reduce carbohydrate tolerance, this disturbance is reversible and probably does not lead to diabetes in non- prediabetic patients. It is possible that the hyperglycemic effect of the thiazides is related to hypoka- lemia. The hyperglycemic effect of thia- zides in both rats48 and man4g has been successfully combated by the administra- tion of potassium supplements. Potassium depletion produced by ion-exchange resin resulted in a decrease in carbohydrate tolerance.50 There is some evidence to suggest that hypokalemia may reduce the production of endogenous in~ulin.5~~51 Other toxic effects which have been ascribed to the benzothiadiazine compounds but which are quite uncommon are der- matitis,52 thrombocytopenic purpura,j3 and pancreatitis.s4 Summary Benzothiadiazine drugs enhance the anti- hypertensive effectiveness of other blood pressure-reducing drugs in man. In the absence of such drugs the antihypertensive effect of benzothiadiazine is of mild degree. The mechanism of the hypotensive action is associated with sodium loss and appar- 262 New York State Journal of Medicine / January 15, 1968 ently not to any direct vasodilator effect. Plasma and extracellular fluid volume re- duction, secondary to the sodium de- pletion, explains part if not all of the anti- hypertensive effect. The principle side-effects of thiazide administration are hypokalemia apparently without significant depletion of body stores of potassium, hyperuricemia due to inter- ference with renal tubular transport mech- anisms for urate, and reduced carbohydrate tolerance. References 1. Hollander, W., Chobanian, A. V., and Wilkins, R. W.: Stud& on the a&hypertensive action of chlorothiazide, Clin. Res. 6: 21 (1958). 2. Rubin. A. A., Roth, F. E., Taylor, R. M., and Roaen- kilde, H.: Pdarmacology of diazoxide, an antihypertennive, nondiuretic benzothiadiazine. J. Pharmacol. & Exwr. Thera~. 136: 344 (1962). 3. Bartorelli. C., Gargano, N., Leonetti, G., and Zan- chetti. A.: Hvnotanaive and renal effects of diazoxide. a sodium-retain& benzotbiadiazine compound, Circula&n 27: 895 (1963). 4. Rowe, G. G., et al.: The systemic and coronary hemo- dynamic effecta of diazoxide, Am. Heart J. 86: 636 (1963). 5. Crdey, A. P. Jr., &al.: The acute effects of carbonic anhvdraae inhibition on systemic hemodynamics, J. Clin. In&. 37: 887 (1958). 6. Dustan. H. P.. Cununine. G. R.. Corcoran. A. C.. and Page, I. H.: A me&hanism o~`cblc&hiazide-e&an& ef- fectiveness of a&hypertensive ganglioplegic drugs, Circula- tion IS: 360 (1959). 7. Froblich, E. D., Schnaper, H. W., Wilson, I. M., and Freis, E. D.: Hemodynamic alterations in hypertensive pa- tients due to chlorothiazide. New England J. Med. 262: 1261 (1960). 8. Freis, E. D.: The effects of salt and extracelltir fluid depletion on vascular responsiveness with particular reference to chlorothiazide, in Sk&on, F. R., Ed.: Hyper- txxxaion. Proc. Council Hieh Blood Pressure Research. NO- vember, 1958, New York, American Heart Association, .1959, vol. 7. 9. Dollery, C. T., Harington, M., and Kaufmann, G.: The mode of action of cblorothiazide in hypertension: with special reference to potentiation of ganglion-blocking agents, Lancet 1: 1215 (1959). 10. 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C.: Long term versus acute hemodynamic effecta of a&hypertensive agents, proceedings of the limt meeting of the International Club on Hypertension, Paris, July 6,1965. 34. T&o, P. J., and Carballo, A. J.: Effects of beneo- thiadiazinea on serum and total body electrolytes, Ann. New York Acad. SC. 88: 822 (1960). 35. Gifford, R. W., Jr., et al.: Effect of thiazide diuretics on plasma volume, body electrolytes, and excretion of aldo- sterone in hypertension, Circulation 24: 1197 (1961). 36. Sones, D. A., Wakim, K. G., Orvia, A. L., and Mc- Gurkin, W. F.: Effects of chlorothiazide on body electro- lyta, Fed. Proc. 19: 249 (1960). 37. Wirier, B. M.: Humoral vasoconstrictor effect of diuretics. Circulation 26: 805 (1962). 38. L&agh, J. H., Heinemann; H. O., and Demartiui, F. E.: Effect of chlorothiazide on electrolyte transport in man: its we in the treatment of edema of congestive heart fail&, nephrosis, and cirrhosis, J.A.M.A. 166: i45 (1958). 39. Demartini, F. E., Wheaton, E. A., He&y, L. A., and Laragh, J. H.: Effect of cblorothiazide on renal excretion of uric acid, Am. J. Med. 32: 572 (1962). 40. Freis, E. D.: Unpublished observations. 41. Finnerty, F. A., Jr.: Discussion, in Moyer, J. H.. Ed.: Hypertension: The First Hahnemann Symposium on Hypertensive Disease, Philadelphia, W. B. Seundera Co.. 1959. p. 663. 42. Shapiro, A. P., Benedek, T. G. and Small, J. L.: Ef- fect of thiazidea on carbohvdrata metabolism in patienta with hypertension, New England J. Med. 266: 1028 TlSSl). 43. Lakin, M., Zeytinoglu, I., Younger, M.D., and White, P.: Effect of chlorothiazide on insulin requirementa of pregnant diabetic women, J.A.M.A. 173: 353 (1960). 44. Wolff, F. W., Parmley, W. W., White, K.. and Okun, R.: Drug-induced diabetes. Diabetogenic activity of long- term administration of benzothiadiazines, ibid. 165: 568 (1963). Carliner N. H. et al.: Thiazide- and phthalimidine- ini&?ed hwer&cemia' in hypertensive patients, ibid. 191: 535 (Feb. is, 1965. 46. Weller, J. M., and Borondy, P. E.: Effects of benzo- thiadiazine drugs on carbohydrate metabolism, Metabolism 14: 708 (June) 1966. 47. Freis, E. D.: Benzothiadiazinea and diabetes melli- tus, J.A.M.A. 187: 462 (1964). January 15, 1968 / New York State Journal of Medicine 263 48. Wolff, F. W., and Parmley, W. W.: Aetiological fac- impaired carbohydrate tolerance, New England J. Med. 273: tom in benzothiadiazine hyperglycaemia, Lane& 2: 69 1135 (Nov. 16) 1965. (1963). 52. Harber, L. C., Laahinsky, A. M., and Baa, R. L.: 49. Ftapaport, M. I.: Thiazide-induced glucaee intoler- Photosensitivity due to cblorothiazide and hydrochlorothi- ance treated with potassium, Arch. Int. Med. 113: 405 wide. ibid. 281: 1378 (1959). (1964). 53. Jaffe, M. D., and Kierland, R. P.: Pwpura due to 50. Sagild, V., Anderson, V., and Andreaem, P. B.: chlomthiazide (Diuril), J.A.M.A. 168: 2264 (1958). Glucoee tolerance and insulin responsivenass in experimental 54. Comish, A. L., McClellan, J. T., and Johnston, D. H.: potassium depletion, Acta med. scandinav. 169: 243 (1961). Effecta of cblorotbiazide cm the pancreas, New England J. 51. Cam, J. W.: Hypertension. the potassium ion and Med.266: 673 (1961). 264 New York State Journal of Medicine / January 15, 1968