REVIEWASOTOI

Non-hormonal drugs for the treatment ofdiabetes insipidus T. Nawar, m.d., m.sc, and J. Genest, cc, m.d., ll.d., f.a.c.p., f.r.c.p.[c], f.r.s.c, Montreal

Summary: Patients with diabetes thazone, clopamide, mefruside, fu¬ by a fall in GFR. Therefore reduc¬ insipidus may be successfully rosemide and ethacrynic acid.3 The tion in GFR does not seem to be the controlled with drugs other than antidiuretic action of mercurials is major mechanism of action although vasopressin. These have the advantage debated. it may play a role in some patients. ofbeing effective when administered Owing to this paradoxical prop¬ A diminished thirst could also ac¬ orally. The most important are the erty natriuretic drugs have been used count partly for the antidiuretic ef¬ diuretics and the hypoglycemic agent in the management of pituitary dia¬ fects; however, even if thiazides chlorpropamide. The mode ofaction, betes insipidus4 although they are less diminished thirst (directly or indirect¬ indications and side effects ofthese effective than vasopressin and are ly) the consequences would not be drugs are reviewed. A third not generally recommended as the great enough to account for the potentially useful agent is clofibrate. sole therapy. They can be very useful, therapeutic results. Also, diminished Recent experience with this drug has however, in combination with other intake of water with continued poly- been described but more observations agents. uria would lead to dehydration and are needed before its possible role in A more important observation stimulation of the thirst mechanism. the management ofdiabetes insipidus from a practical standpoint is that Attempts to alleviate diabetes insi¬ can be established. diuretics induce the same antidiure- pidus by voluntary restriction of sis in patients with nephrogenic water intake are generally unsuccess- (vasopressin-resistant) diabetes insi¬ ful. Diabetes insipidus is classically treat¬ pidus.4 They are actually the only Another mechanism of action pro¬ ed by replacement therapy with vari¬ effective drugs in this situation. posed by Senft et al6 is through an ous preparations of posterior pitu¬ The mechanism of this antidiuretic increase in cyclic-3'5'-adenosine itary hormones.1 Recently a number action is not fully understood. The monophosphate (cyclic-AMP). Thia¬ of drugs unrelated to vasopressin suggestion that they have a direct zides have been shown to inhibit have been shown to possess antidiure¬ action on the distal nephron2 is in¬ phosphodiesterase in the kidney, tic properties when administered to compatible with their effectiveness in causing an accumulation of cyclic- patients with diabetes insipidus. Their patients with nephrogenic diabetes AMP, believed to be the mediator main advantage is that they are ef¬ insipidus. Some vasopressin-like ac¬ of the antidiuretic action of vasopres¬ fective when administered orally. tivity of thiazides has been demon¬ sin. However, the effects of thiazides strated in vitro on isolated toad blad¬ on urine osmolality and free water A. Diuretics der and frog skin. In other experi¬ clearance are markedly different Chlorothiazide was the first diuretie ments thiazides had no effect on from those of vasopressin. In addi¬ found to depress free water clearance sodium transport across the toad tion this mechanism could not ex¬ (Ch2o) when administered to normal bladder but had some inhibitory plain the beneficial effect of thia¬ subjects during water diuresis. Soon action on aldosterone-stimulated zides in nephrogenic diabetes insipi¬ afterwards a chronic antidiuretic ef¬ sodium transport. This led to the dus where there seems to be a defect fect of chlorothiazide was observed postulation of an antimineralocorti- in the response to cyclic-AMP. in both experimental and clinical coid effect of thiazides on the renal The most important mechanism diabetes insipidus.2 This effect is not tubule. However, this was not sup¬ for the antidiuretic effect of diuretics unique to chlorothiazide but was also ported by subsequent observations5 in diabetes insipidus is probably the demonstrated with hydrochlorothia¬ and the natriuretic effect of thiazides sodium depletion induced by these zide and practically all known thia¬ is not dependent on the presence of drugs. The antidiuretic effect is en¬ zide diuretics, spironolactone, quine- the adrenals. hanced by sodium deprivation5 and A decrease in glomerular filtration reduced or abolished by sodium load¬ From the Clinical Research Institute of rate (GFR) is sometimes observed ing. It should be recalled that pa¬ Montreal. after thiazide administration, but tients with diabetes insipidus reduce t. nawar, fellow ofthe Medical Research there was no correlation between the their when on a Council ofCanada. urinary output kept decrease in GFR and the antidiuretic low-sodium diet even in absence of Reprint requests to: Dr. Jacques Genest, Scientific Director, Clinical Research Institute effect observed in patients with dia¬ other therapy.5 However, treatment ofMontreal, 110 Pine Avenue West, betes insipidus.4 In dogs the anti¬ of rats with experimental diabetes Montreal 130, P.Q. diuretic effect is not accompanied insipidus with hydrochlorothiazide C.M.A. JOURNAL/DECEMBER 23, 1972/VOL. 107 1225 and sodium supplements resulted in tracellular volume.13 It also differs The antidiuretic effect first noted the same antidiuretic effect as the from thiazides in being ineffective in with chlorpropamide has also been thiazide without salt supplement. patients with nephrogenic diabetes reported with tolbutamide and di- Furthermore, sodium supplements insipidus.12 guanides. Surprisinglyglibenclamide, sufficient to prevent sodium deple- Many toxic reactions have been a new potent hypoglycemic drug of tion did not prevent the antidiuretic recorded with chlorpropamide ther¬ the sulfonylurea group, was recently activity of benzoflumethiazide in a apy, the most important being the observed to aggravate rather than patient with pituitary diabetes insi¬ occurrence of hypoglycemia. This reduce the polyuria in patients with pidus. Despite these observations occurs more frequently in children pituitary diabetes insipidus.21 sodium depletion is presently the and in patients with anterior pitui¬ The mechanism by which chlorpro¬ most generally accepted explanation tary insufficiency and seems to be pamide potentiates the effect of vaso¬ for the decrease in urinary output dose-related.14* 15 One way to avoid pressin is not clear. Sulfonylureas induced by diuretics in patients with this problem is to give chlorpropa¬ have been shown to inhibit adenosine diabetes insipidus. mide in combination with a thiazide. 3'5'-cyclic monophosphate phospho- The mechanism by which sodium This has two advantages: first, the diesterase, thereby reducing the rate depletion leads to antidiuresis is not antidiuretic effect of the thiazide will of degradation of cyclic-AMP, but fully understood. Increased produc¬ allow a reduction in the dose ofchlor¬ only at high concentrations. This was tion of aldosterone can be excluded propamide and second, the hyper- observed in kidney and other tis¬ since the antidiuretic effect is not glycemic effect of the thiazide will sues.22, 23 Not all the actions of sul¬ abolished by adrenalectomy nor by counteract the tendency to hypogly¬ fonylureas can be explained by this concomitant administration of aldo¬ cemia. We have followed a patient mechanism.23 In addition, although sterone antagonists.1 The action of with this combination therapy for chlorpropamide enhances the action angiotensin has been suggested as a more than two years. Not a single of vasopressin on the isolated toad mechanism7 since angiotensin is hypoglycemic episode has occurred bladder it does not enhance the effect known to be antidiuretic under cer¬ in spite of concomitant anterior of cyclic-AMP on this preparation. tain circumstances in normal indi¬ pituitary insufficiency.16 Favourable This suggests a site of action "proxi¬ viduals as well as in patients with results with this combination have mal" to cyclic-AMP within the recep¬ diabetes insipidus. This explanation been reported by others.15 tor cell where it may act by increasing is considered unlikely by others.8 The mechanism of the antidiuretic the sensitivity of adenylcyclase to The most likely mechanism is con¬ effect of chlorpropamide has been vasopressin. The picture is further traction of the extracellular fluid vol¬ the subject of several studies. The complicated by reports showing that ume secondary to loss of sodium most mechanism seems to be chlorpropamide may inhibit the re¬ induced the diuretics.9 This is likely by potentiation of the effect of vaso¬ sponse of the isolated toad bladder known to cause increased reabsorp¬ pressin on the distal nephron. This to cyclic-AMP and that it may even tion of sodium and water from the view is supported by several obser¬ exert a direct effect on this prepara¬ proximal tubule,10 so that a smaller vations. The antidiuretic effect is de¬ tion. volume is delivered to the distal creased by procedures capable of One other practical aspect of this tubule, with a subsequent diminution antidiuretic of is its in urine flow. decreasing endogenous property chlorpropamide hormone (ADH) release (water load¬ possible occurrence as an undesirable Patients receiving thiazides also alcohol and is increas¬ effect in patients with diabetes mel¬ exhibit an to ex- ing, ingestion) impaired capacity ed by procedures which increase en¬ litus treated with this drug; the clini¬ crete a water load, due to inhibition ADH release de¬ cal of ADH of sodium in the dilut- dogenous (water picture inappropriate reabsorption It does not occur in rats secretion results. recent re¬ of the This is privation).17 Indeed, ing segment nephron.11 of the Brattleboro strain (with a ports suggest that this complication of practical importance since exces¬ defect in ADH is not uncommon.24 sive water intake under these circum¬ congenital synthesis) which are totally in stances lead to severe dilutional lacking endog¬ may enous vasopressin, but chlorpropa¬ C. Clofibrate hyponatremia.11 mide does potentiate the antidiuretic Clofibrate (chlorophenoxyisobuty- effect of small doses of vasopressin rate) has been used as a lipid-lower- B. Chlorpropamide in these rats. Similar observations ing drug for years. In 1969 DeGennes The antidiuretic property ofchlorpro¬ have been reported using water-load- et al noted, during the treatment of pamide in diabetes insipidus was ed dogs. The agent is less antidiuretic a patient suffering from both diabetes noted fortuitously by Arduino, Fer- in patients in whom pituitary diabe¬ insipidus and hypercholesterolemia, raz and Rodriguez in 1966.12 Since tes insipidus is most severe.15'17 As a marked antidiuresis. After receiv¬ then the clinical efficacy of this drug mentioned previously it has no anti¬ ing clofibrate the patient noticed a has been amply demonstrated and it diuretic action in patients with ne¬ marked improvement in her diabetes has been successfully used by many phrogenic diabetes insipidus. The insipidus and could even discon¬ groups. Unlike thiazides it causes claim that chlorpropamide may in¬ tinue the vasopressin injections she reduction in the excretion of water crease the synthesis and release of had been receiving for several years. without changing the glomerular fil- ADH18 is not supported by recent The same observation was made in tration rate or the solute excretion. studies of the direct measurement two other patients with diabetes in¬ Its antidiuretic effect therefore re- ofcirculating vasopressin levels.19 sipidus treated with clofibrate.26 The sembles that of vasopressin and is Chlorpropamide also increases drug was given at a dose of 1.5 to not dependent upon negative sodium thirst, an advantage for patients with 2.25 g./day and each patient demon¬ balance and contraction of the ex¬ diabetes insipidus and hypodipsia.20 strated a striking reduction in urin- 1226 C.M.A. JOURNAL/DECEMBER 23, 1972/VOL. 107 ary volume and increase in urinary des cas de diab&te insipide par des with chlorpropamide. CalifMed 115: 1-5, osmolality; free water clearance be- medicaments autres que la vasopres- 1971 16. NAWAR T: M.Sc. Thesis, McGill Universi- came negative. These effects were less sine. Ces m6dicaments ont l'avantage ty, Montreal, 1971 evident in four water-loaded normal d'etre efficaces par voie orale. Parmi 17. MILLER M, MOSES AM: Mechanism of subjects. les plus importants, on peut citer les chlorpropamide action in diabetes in- We have used this drug in one pa- diuretiques et l'hypoglycemiant oral, sipidus. J Clin Endocrinol Metab 30: tient with pituitary diabetes insipidus le Les 488-496, 1970 chlorpropamide. auteurs rap- 18. ETTINGER B, FORSHAM PH: Mechanism of and observed a drop in urine volume pellent le mode d'action, les indica- chlorpropamide antidiuresis in diabetes in- and free water clearance and a rise tions et les effets secondaires de ces sipidus. J Clin Endocrinol Metab 31: in urinary osmolality. There was no medicaments. Un troisieme medica- 552-555, 1970 change in urinary sodium excretion ment utile dans ce domaine est le 19. ROBERTSON GA, MAHRE A: Mechanism of chlorpropamide antidiuresis in diabetes or creatinine clearance. The anti- clofibrate, dont on fait mention dans insipidus: studies with a new radioim- diuretic effect was rapid (starting des experiences recentes. Il faudra munoassay for plasma vasopressin (ab- within the first 24 hours) and was cependant plus d'observations avant stract no 125). 53rd Meeting of the En- abolished by concomitant water- de pouvoir etablir son role possible docrine Society, San Francisco, 1971 loading or ethanol administration, dans le traitement du 20. MAHONEY JH, GOODMAN AD: Hyperna- diabete in- tremia due to hypodipsia and elevated suggesting a mechanism of action in- sipide. threshold for vasopressin release. N EnglJ volving endogenous ADH.'6 This is Med 279: 1191-1196, 1968 supported by the preliminary ob- 21. RADO JP, BORBELY L: Enhancement of servation that clofibrate was ineffec- polyuria by glibenclamide in diabetes in- References sipidus. Lancet II: 216, 1971 tive in rats with congenital diabetes 1. LEAF A, COGGINS CH: The neurohypoph- 22. BROCKER G, FICHMAN M: Chlorpropa- insipidus.'6 The rapid onset of the ysis, in Textbook ofEndocrinology, edited mide and tolbutamide inhibition ofadeno- antidiuretic effect, also observed by by WILLIAMS RH, Philadelphia, WB Saun- sine 3'5'-cyclic monophosphate phos- DeGennes et al,2" is interesting be- ders, 1968, p 85 phodiesterase. Biochem Biophys Res cause the lipid-lowering effect is slow 2. CRAWFORD JD, KENNEDY GC: Chloro- Commun 42: 824-828, 1971 thiazide in diabetes insipidus. Nature 23. ROTH J, PROUT TE, GOLDFINE IE, et al: and takes several weeks. This sug- (Lond) 183: 891-892, 1959 Sulfonylureas: effects in vivo and in vitro. gests that the two actions are prob- 3. PETERS G, ROCH-HAMEL F: Thiazide diu- Ann Intern Med 75:607-622, 1971 ably unrelated. retics and related drugs in Handbuch der 24. WEISSMAN FN, SHENKMAN L, GREGER- It is interesting to note that weight Experimentellen Pharmakologie (vol 24, MAN RI. Chlorpropamide hyponatremia: diuretica). Springer-Verlag, p 257, 1969 drug-induced inappropriate antidiuretic- gain has been observed in patients 4. EARLEY LE, ORLOFF J: Thiazide diuretics. hormone activity N Engi J Med 284: receiving clofibrate for the treatment Ann Rev Med 15:149-166, 1964 65-71, 1971 of hyperlipidemia. Although total 5. Idem: The mechanism of antidiuresis 25. DEGENNES JL, BERTRAND C, BIGORIE B, body water as well as plasma volume associated with the administration of et al: Etudes pr6liminaires de l'action an- hydrochlorothiazide to patients with vaso- tidiuretique du clofibrate (ou Atromid S) were reported to be unchanged more pressin-resistant diabetes insipidus. J Clin dans le diabete insipide pitressosensible. studies are needed to exclude the Invest 41: 1988-1997, 1962 Ann Endocrinol(Paris) 31: 300-308, 1970 possibility that clofibrate-induced 6. SENFT G, MUNSKE K, SCHULTZ G, et al: 26. DECOURT MJ: Avantage du clofibrate antidiuresis may contribute to the Der einflu# von hydrochlorothiazid und dans un cas de diab6te insipide. Ann En- weight gain. anderen sulfonamidierten diuretics auf die docrinol(Paris) 32: 284-289, 1971 3'5'-AMP phosphodiesterase-aktivitat in 27. KAHN BS: The use ofaminopyrine in a case The number of observations relat- der rattenniere. Arch Pharmak Exp Path of diabetes insipidus. JAMA 100: ed to the antidiuretic effect of clo- 259: 344-358, 1968 1593-1594, 1933 fibrate is very limited and its long- 7. BROWN JJ, CHINN RH, LEVER AF, et al: 28. NUSYNOWITZ ML, FORSHAM PH: The an- term remains Antidiuresis in diabetes insipidus. Lancet tidiuretic action of acetaminophen. Am J efficacy to be estab- I: 729, 1968 Med Sci 252: 429-435, 1966 lished. However, this drug may have 8. MORGAN T, DEWARDENER HE: Anti- 29. DELZANT G, SEBAOUN J, KRIVITZKY N: a useful place in the management of diuresis in diabetes insipidus. Lancet I: Utilisation du carbamoyl-dibenzo-azepine patients with diabetes insipidus, par- 524-525, 1969 (Tegretol) dans la therapeutique du diab6te ticularly those in whom 9. DAVIDOV M, GAVRILOVICH L, MROCZEK insipide. A nn Endocrinol (Paris) 32: chlorpropa- W, et al: Relation of extracellular fluid 540-546, 1971 mide causes troublesome hypogly- volume to arterial pressure during drug- cemia.26 induced saluresis. Circulation 40: 349-355, 1969 Other drugs 10. WEINER MW, WEINMAN EJ, KASHGARIAN M, et al: Accelerated reabsorption in the Several other agents have been de- proximal tubule produced by volume de- scribed as possessing antidiuretic pletion. J Clin Invest 50: 1379-1385, 1971 properties, but they are not used gen- 11. KENNEDY RM, EARLEY LE: Profound hy- erally for the treatment of diabetes ponatremia resulting from a thiazide- induced decrease in urinary diluting capac- insipidus because of toxic side effects ity in a patient with primary polydipsia. N or insufficient data concerning their EnglJ Med 282: 1185-1187, 1970 potential use in this situation. These 12. ARDUINO F, FERRAZ FPJ, RODRIGUEZ J: include aminopyrine,27 acetamino- Antidiuretic action of chlorpropamide in idiopathic diabetes insipidus. J Clin Endo- phen28 and the anticonvulsant drug crinol Metab 26: 1325-1328, 1966 carbamazepine.29 13. EARLEY LE: Chlorpropamide antidiuresis. NEnglJMed284: 103-104, 1971 Resume 14. REIMOLD EW: Chiorpropamide in the Medicaments non hormonaux pour treatment of diabetes insipidus in children. AmJDisChildl120: 103-108, 1970 le traitement du diabe~te insipide 15. CUSHARD WG, BEAUCHAMP CJ, MARTIN I1 est possible de traiter avec succes ND: Oral therapy of diabetes insipidus 1230 C.M.A. JOURNAL/DECEMBER 23, 1972/VOL. 107