Postgrad Med J: first published as 10.1136/pgmj.36.416.392 on 1 June 1960. Downloaded from

392 THERAPEUTIC SYMPOSIA-2: NEW DIURETICS

HYDROCHLOROTHIAZIDE & HYDROFLUMETHIAZIDE JOAN F., ZILVA, B.Sc., M.D., M.R.C.P. Department of C1h4mical Pathology, Westminster Hospital Medical School, S.W. I

Pitts2O has defined a diuretic as an agent which In 1958 de Stevens et al.3 synthesized dihydro- promotes urinary excretion of sodium and chloride chlorothiazide which only differed from chloro- or bicarbonate with secondary loss of water. thiazide in having the double. bond in the 3: 4 These ions are, as he points out, the major ones position saturated with two hydrogen atoms, and in the extra-cellular fluid, and it may be added following a pattern now familiar in other fields, that the ideal diuretic would result in excretion of a further attempt was made to alter the action of urine (over and above the base line levels) of the drug by substituting a trifluoromethyl group composition as near as possible to that of this for the chlorine atom in position 6 of the hydro- fluid. Rees24 has called this the ' ideal diuretic chlorothiazide molecule. fluid '. Preliminary trials on animals3 suggested that

Since Vogl first noted that a syphilitic patient these new derivatives had less inhibitory effect on copyright. treated with organic mercurials experienced a carbonic anhydrase than the parent substance, diuresis, diuretics of this type have been widely and therefore that both potassium and bicarbonate used with great success. However, the poor loss were reduced. It was hoped that the problem absorption and the irritant effect of this group of of hypokalaemia encountered so often in the use substances on the gastrointestinal tract necessitate of chlorothiazide would be overcome. However, the expense and discomfort of parenteral ad- as will be shown, these hopes have not been ministration. For some years attempts were made realised. There is apparently no difference in to find a potent oral diuretic, but most of these, practice between hydrochlorothiazide and hydro- http://pmj.bmj.com/ such as the pure carbonic anhydrase inhibitors, flumethiazide and they will therefore be discussed had serious disadvantages. However, in 1957 together. Novello and Sprague'9 synthesised chlorothiazide (6-chloro-7-sulphamyl-I, 2, 4-benzothiadiazine-I, i-dioxide), which, in spite of its sulphonamido Mode of Action (-SO2NH2) group seemed to have only a mild As has been stated above, by virtue of its inhibitory effect on carbonic anhydrase. By far -SO2NH2 group chlorothiazide has some inhibitory its most potent action seemed to be an inhibition effect on carbonic anhydrase. This enzyme cata- on September 29, 2021 by guest. Protected of sodium and chloride reabsorption in the renal lyses the reaction. tubules similar to that of the mercurials. How- CO2 + H20 = H2C03 ever, as might be expected, the presence of the in the renal tubule. Ionisation of H2CO3 to H + icarb6nic anhydrase inhibitory effect does result in and HCO-3 makes available hydrogen ions for greater loss of potassium than with mercurials exchange with cations such as sodium and potas- (though this is much less than with the pure sium in the glomerular filtrate, and reabsorption carbonic anhydrase inhibitors such as acetazol- of NaHCO3 and KHCO3 results. If the enzyme amide). Clinical trials repeatedly demonstrated is inhibited, potassium and bicarbonate as well as that while chlorothiazide was the most satisfactory sodium will be lost in the urine. This occurs to and safest oral diuretic so far discovered; yet there a large extent with acetazolamide, and much less was a real danger of potassium depletion, especially so with chlorothiazide. With hydrochlorothiazide in cases with severe secondary aldosteronism such and hydroflumethiazide this action is still less, but as advanced congestive cardiac failure or hepatic' bicarbonate loss is diminished much more than cirrhosis, or those on strict sodium restric- that of potassium. Therefore, the effect of the tion.', 16,23,26,27 chlorothiazide group on excretion of this cation Postgrad Med J: first published as 10.1136/pgmj.36.416.392 on 1 June 1960. Downloaded from June 1960 ZILVA: Hydrochlorothiazide and Hydroflumethiazide 393

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0i- 03- Chlorothiazide Hydrochlorothiazide Hydrof2lumethiazide

cannot' wholly be due to inhibition of carbonic choose between chlorothiazide on the one hand,. anhydrase. and hydrochlorothiazide and hydroflumethiazide The'Ts mercurial-.like effect of chlorothia'zide and on the other, if differences in potency are allowed its derivatives on the''reabsorption of sodium and for.88 2, 6, 7, 13,15 Water excretion is secondary chloride has.not been elucidated. Pitts2o points to loss of these ions. out that its action and that of the mercurials is -- However, the 'ideal.' diuretic results in an additive, and that they may, therefore, act at increased urinary loss of electrolytes in proportion different parts *of the tubule, or on different to their concentrations in the extra-cellular fluid mechanisms at the same part. Labelled hydro- that is, the ratio of Na Cl: HCO' in the urine chlorothiiazid has been shown to collect in the should be approximately 140 : 100: 30. Any drug distal' 1f'rt 6f -th proximal -con.yoluted' ul;s.4 which alters these ratios will tend to. cause a disturbance of acid-base balance. Thus acetazol- Potency, Dosage and Duration of 4Action amide, by increasing the excretion of bicarbonate Aft w.orkers agree that weigl'kt for weight hydro- in proportions greater than those given above, chlorothiazide and hydroflumethiazide'are Io to frequently causes a 'hyperchloraemic acidosis, 20 times as potel fas"chlorothizidde. 3,2, 5, 7, 8;i, 21 while the use of mercurials, which results in very

This in-itself is of no-great advawege-since chioro- little bicarbonate excretion may lead to hypo- copyright. thiazide is of an adequate potency. The fact that chloraemic alkalosis; both of these conditions are the p'atient is obliged to swallow a smaller tablet is associated with the development,.of resistance to not, in itself, a worthwhile outcome of the amount the drug. Chlorothiazide, by virtue of its mild of research done on the subject. It has been carbonic anhydrase inhibitory effect causes more claimed that hydrochlorothiazide and hydro- loss of bicarbonate. than the- mercurials, and flumethiazide have a more prolonged action than although the ratio of sodium to- chloride is about chlorothiazide,6' 28 and this might be an advan- I to i; trials'have shown little or no tendency to

tage. However, this effect seems 'to Us to be acid-base disturbances. However, both its derivra- http://pmj.bmj.com/ variable.. Individual -differences between-subjects tives under consideration here have little effect on make this sqrt of difference difficult to assess. bicarbonate excretion, and both sodium and The greater potency of hydrochlorothiazide and potassium are lost mainly in the form of chloride. hydroflumethiazide is almost certainily associated It has repeatedly been observed that with these with the fact that a larger percentage of a -given two. drugs more chloride than sodium is ex- dose appears in.the urine than with chlorothia- creted,, I6s'13, 29 and as might be-predicted: there zide.28 This may be due to more efficient absorp- have been reports of the development of hypo- tion from the--intestine, or perhaps to the fact that chloraerwa.21, It may be that this will prove on September 29, 2021 by guest. Protected while chlorothiazide is excreted in the bile, its to be a drawback of long continued use of hydro- derivatives are not, and thus more is available for chlorothiazide and hydroflumethiazide. renal excretion.7 Dose-response curves8' 13, 17 seem to show that Potassium while there is an increasing diuretic response.with As has been stated above, hypokalaemia is the up to 50 or i00 mg. of the drug, no advantage is greatest hazard of chlorothiazide therapy, and-it to be gained from administration of larger doses. was hoped that the risk might be less with-its,, derivatives. However, this has not proved to. be Renal Loss of Electrolytes , 11,21,29 and potassium supplements should Sodium, Chloride and Bicarbonate be 'given with these drugs. The greatest loss of The efficiency of a diuretic is judged by its potassium occurs in patients with marked second- ability to increase the excretion of sodium and ary hyperaldosteronism, particularly those with chloride by the kidneys, and using this criterion, hepatic cirrhosis, in which the drug may precipi- there is no doubt that all the chlorothiazide group tate hepatic coma, possibly as a secondary result are very effective. In this respect there is little to of hypokalaemia.23 15 Potassium loss is also aggra- Postgrad Med J: first published as 10.1136/pgmj.36.416.392 on 1 June 1960. Downloaded from 304 POSTGRADUATE MEDICAL JOURNAL Yune I960 vated in subjects on strict sodium restriction, effects. The more serious complications of since less sodium is then available to balance the agranulocytosis and thrombocytopenic purpura excretion of chloride and the deficit is largely have also been reported with chlorothiazide,30 18 made up of potassium. but these are very rare, and have not yet been For these reasons, patients treated with the reported with the analogues. chlorothiazide analogues should receive potassium supplements, probably on the days between the Summary doses of the diuretic,22 and should be allowed salt in their diet. In addition, care should be taken Hydrochlorothiazide and hydroflumethiazide with digitalis therapy, since sensitivity to this drug are relatively safe oral diuretics. is increased by potassium depletion.29 Weight for weight, they are more potent than In passing it may be noted that some potassium chlorothiazide. loss occurs with mercurials, but that the much Compared with the latter, the tendency to lower incidence of hypokalaemia in patients treated produce urinary potassium loss is not significantly with them may be due to the fact that these reduced. intervals than drugs are usually given at longer REFERENCES chlorothiazide and its derivatives. I. BAYLISS, R. I. S., MARRACK, D., PIRKIS, J.. REES, J. R., and ZILVA, J. F. (I958), Lancet, i, I20. Other Effects 2. BLAGG, C. R., (1959), Ibid. ii, 3 1. 3. DE STEVENS, G., WERNER, L. H., HALAMANDARIS, Effect on Serum Uric Acid A., and RICCA, S. (i9s8), Expsrientia (Basel), 14, 463. 4. DARMADY, E. M., and GAUNT, R. (1959), Conference on Hyperuricaemia has been reported during the ' Diuresis and Diuretics,' Lanet, ii, 279. use of hydrochlorothiazide as with chlorothiazide, 5. DOLLERY, C. T., HARINGTON, M., and KAUFMANN, in patients with renal disease.259 29 How- G. (I959j), Lactnet, i, 121S. usually 6. EDMONDS, C. J., and WILSON, G. M. (i9S9), Ibid., ii, 303. ever, clinical gout has rarely been observed and 7. FLEMING, P. R., ZILVA, J. F., BAYLISS, R. I. S., and this finding is probably of little significance. PIRKIS, J. (I959), Ibid., i, 12I8. 8. FORD, R. V. (I959), Sth. med. Y., 52, 40. Effect on the Blood Pressure 9. HALL, R., and OWEN, S. G. (i9S5), Lancet, i, 129. io. HARINGTON, M., and KINCAID-SMITH, P. (1958), copyright. has been reported to potentiate Ibid., 1, 403. Chlorothiazide iI. HAVARD, C. W. H., and FENTON, J. C. B. (I95s), Brit. ganglion-blocking agents used in the treatment of med.Y.i,I, s560. hypertension by decreasing their excretion, and 12 -JONES, J. H., and JONES, J. B. (i959), Ibid., ii, 928. 13. KENNEDY, A. C., WATSON, W. C., and CUNNINGHAM, has also been reported to have a primary hypo- C. (19s5), Lancet, ii, 309. tensive effect, possibly due to a reduction in plasma 14. KENNEDY, G. C., and CRAWFORD, J. D. (I9g9), Ibid., 9 i, 866. volume.10' 5, Similar effects have been described IS. KERR, D. N. S., READ, A. E., and SHERLOCK,' S. (is95), for hydrochlorothiazide and hydroflumethia- Ibid., i, 1221. i6. MATHESON, N. A., an-' MORGAN, T. N. (I958), Ibid., i, zide.2' 29 I I95. http://pmj.bmj.com/ 17. MOYER, J. H., FUCHS, M., IRIE, S., and BODI, T. (is5), Effect in Diabetes Insipidus Amer. Y. Cardiol., 3, 113. i8. NORDQVIST, T. P., CRAMER, G., and BJORNTORP, P. Kennedy and Crawfordl4 have claimed that in (i959), Lancet, i, 271. I9. NOVELLO, F. C., and SPRAGUE, J. M. (1957), _T Amer. diabetes insipidus chlorothiazide and hydro- chem. Soc., 79, 2028. chlorothiazide have an antidiuretic effect, and 20. PITTS, R. F. (I958), Amer. Y. Med., 24, 745. suggest that these drugs could be used in treat- 21. PLATTS, M. M. (I959g), Brit. med. Yt., i, I 56S. 22. POZNANSKI, W. J., and CROMIE, B. W. (i959), Ibid., i, ment of the disease. Further reports are awaited, 1553. but in one case seen at Westminster Hospital this 23. READ, A. E., HASLAM, R. M., LAIDLAW, J., and SHER- on September 29, 2021 by guest. Protected LOCK. S. (1958), Ibid., i, 963. effect has not been confirmed. 24. REES, J. R. (i959), 'Studies with Chlorothiazide,' p. S7, M.D. thesis, University of Cambridge. 25. SACKNER, M. A., WALLACK, A. A., and BELLET, S. Toxicity (I959), Amer. 7. med. Sdi., 237, 575. The toxicity of the chlorothiazide group of 26. SLATER, J. D. H., and NABARRO, J. D. N. (1958), Lancet. i, 124. drugs is very low. The greatest danger, as stressed 27. WATSON, W. C., THOMSON, T. J., and BUCHANANP above, is potassium depletion, especially in the J. M. (1958), Ibid., i, II99. 28. YOUNG, D. S., FORRESTER, T. M., and MORGAN, case of hepatic cirrhosis. There have been reports T. N. (1959), Ibid., ii, 765. of mild gastrointestinal symptoms such as abdomi- 29. ZATUCHNI, J., KING, W., and RESINSKI, M. (X959)> and transient skin Amer. J7. med. Sc,., 237, 479. nal distension and flatulence2l 30. ZUCKERMAN, A. J., and CHAZAN, A. A. (I958), Brit. med. irritation.6 These are rare and unimportant side 7., ii, 1338.