Magnesium-Bulletin 4/84 Leary et. al. I Hydrochlorothiazide and amiloride combination on plasma magnesium 127

Effects of a hydrochlorothiazide and amiloride combination on plasma magnesium in patients with essential hypertension

By W. P. Leary, A. J. Reyes and K. van derBy/ University of Natal, Durban, South Africa, and Universidad de la Republica and Fundaci6n Procardias, Montevideo, Uruguay

Zusammenfassung treated group and six out of ten of the pa­ deployment of these substances Bei 21 ambulanten Patienten wurde tients in the HCTZ+AMl-treated group is not devoid of important side­ der EinfluB von 50 mg Hydrochlorothia­ exhibited plasma Mg concentrations be­ low 0. 75 mmoi.L - 1, after a mean duration effects [26, 27], amongst which zid allein (H) und in Kombination mit bodily Mg depletion is one of the 5 mg Amilorid (H +A) auf das Verhalten of treatment of 22 weeks. No significant des Plasma-Mg untersucht. Die Patienten differences existed between the effects most relevant [28]. Common wurden zufallig und unter Doppelblind­ the studied formulations had on plasma loop (e.g. furosemide) and distal M g. bedingungen den beiden Behandlungsar­ lt is concluded that the addition of tubular (e.g. hydrochlorothiazide, ten, die 23 Wochen tang durchgefiihrt chlorthalidone) diuretics have wurden, zugeordnet und erhielten taglich 5 mg amiloride to 50 mg hydrochlorothia­ zide does not help preventing the fall in been found to cause hypermag­ je eine Tablette. plasma Mg induced by 50 mg hydrochlo­ Beide Therapieformen waren am Ende nesiuresis in acute and chronic der Beobachtungszeit gleichermaBen an­ rothiazide upon prolonged administra­ studies carried out in normal tihypertensiv wirksam, obwohl die hypo­ tion. subjects and in patients suffering tensive Wirkung der Kombinationsbe­ from various conditions [28, handlung (H +A) schneller einsetzte. Resume Nach durchschnittlich 22 Wochen fiel 30, 34]. The ensuing bodily Mg L'effet de 50 mg d' hydrochlorothiazide depletion is the principal deter­ das Plasma-Mg in der (H)-Gruppe von (HCTZ) et celui d'une combinaison de 0,77 auf 0,70 mmol/1 (p < 0,05) und in der 50 mg d'hydrochlorothiazide et 5 mg minant of diuretic-induced car­ (H + A)-Gruppe von 0,82 auf d'amiloride (HCTZ+ AMI) sur le Mg diac arrhythmias (hitherto as­ 0,75 mmol/ 1 (p < 0,05). Sieben von neun plasmatique etaient etudies chez vingt­ cribed to K depletion) [24, Patienten der (H)-Gruppe und sechs von et-un malades ambulatoires avec hyper­ 28, 30], hampers the antihyper­ zehn der (H + A)-Gruppe hatten Plasma­ tension arterielle essentielle. Les malades Mg-Konzentrationen unter 0,75 mmol/ 1 etaient assignes, par hasard et douple­ tensive effect of diuretics [6], nach durchschnittlich 22 Behandlungs­ aveugle, au traitement avec HCTZ ou contributes to shifting the plasma wochen. Hinsichtlich des Plasma-Mg be­ HCTZ+AMT une fois par jour, pendant lipid profile towards a pattern of stehen zwischen der (H)- bzw. (H + A)­ 23 semaines. Gruppe keine signitikanten Unter­ high cardiovascular risk [28], and Les deux formulations montrerent des predisposes to sudden death and schiede. efticacies antihypertensives de la meme Es wird gefolgert, dal3 bei Langzeitbe­ magnitude finale, bien que l'effet de coronary and cerebrovascular handlung die zusatzliche Gabe von 5 mg l'HCTZ+AMI etait plus rapide que celui spasms [1, 7, 16, 18]. Amilorid nicht die durch 50 mg Hydro­ de l'HCTZ. La concentration plasmati­ chlorothiazid verursachte Abnahme des que du Mg tomba d'une moyenne de The K-sparing diuretic amilor­ Plasma-Mg verhindert. 0.77 mmol.L-1 avant le traitement a ide exhibits weak dose-depend­ 1 0.70 mmol.L- (p< O.OS) apn!s une ent, Mg-sparing actions when Summary moyenne de 22 semaines de therapie avec HCTZ. Pendant le meme periode, le ma­ single doses are administered to The effects on plasma Mg of 50 mg hy­ gnesium plasmatique descendu de 0.82 a healthy individuals [8, 17], wher­ drochlorothiazide (HCTZ) and those of a 0.74 mmoi.L- 1 (p <0.05) chez les malades 50 mg hydrochlorothiazide and 5 mg amil­ eas hydrochlorothiazide 50 mg traites avec HCTZ+AMT. Sept des neuf (HCTZ) causes significant hyper­ oride combination (HCTZ+ AMI) were malades traites avec HCTZ et six des dix studied in twenty-one ambulant patients des malades traites avec HCTZ + AMI magnesiuresis under similar ex­ suffering from essential hypertension. Pa­ eurent chiffres de Mg plasmatique infe­ perimental circumstances [ 15]. A tients were double-blind and randomly rieures au· limite normal de combination of 50 mg hydro­ allocated to treatment with one daily ta­ 0.75 mmol.L-1, apres une moyenne de blet of either formulation, for a 23-week chlorothiazide and 5 mg amilor­ 22 semaines de traitement. ide (HCTZ +AMI) has not been period. On conclut que !'addition de 5 mg Both formulations exerted equally effi­ d'amiloride ne previent pas la chute du found to induce a statistically cacious tinal antihypertensive effects, Mg plasmatique provoque par !'adminis­ significant increase in magnesi­ though the hypotensive action of tration journaliere de 50 mg d'hydrochlo­ uresis when a single dose is given HCTZ+ AMI proceeded at a higher rate rothiazide. than that of HCTZ. to normal subjects [10, 16]. In After an average of 22 weeks of ther­ consequence, it could be postu­ apy, plasma Mg fell from a pretreatment lated that HCTZ+AMI would Introduction mean value of 0.77 to 0.70 mmoi.L- 1 be less likely to induce a de­ (p < 0.05) in the HCTZ-treated group, and from 0.82 to 0.74 mmoi.L-1 (p<0.05) Diuretics are widely used in crease in bodily Mg than HCTZ, in the HCTZ+AMI-treated group. Seven the treatment of essential hyper­ when given chronically to hyper­ out of the nine patients in the HCTZ- tension. However, the chronic tensive patients. 128 Leary et al. I Hydrochlorothiazide and amiloride combination on plasma magnesium Magnesium-Bulletin 4/84

The objective of this study was diabetes mellitus requiring phar­ telet estimation and standard to comparatively assess the ef­ macological treatment; (xvi) urinalysis. Blood samples for fects of HCTZ+AMI and of rheumatic conditions requiring laboratory analyses were taken HCTZ on plasma Mg, during drug therapy; (xvii) respiratory 2-4 h after the last intake of medium-term administration to disorders requiring drug treat­ medication. patients with essential hyperten­ ment other than with antibiotics; sion. (xviii) anaemia or leucopenia; (xix) conditions requiring topical Operational procedures Patients and methods application of corticosteroids; (xx) any severe disease likely to At the first examination pa­ Patients interfere with the objectives of tients who were under antihyper­ Twenty-one males, clerical or the study, either per se or be­ tensive treatment had current manual workers, aged 35 to 56 cause of the necessary medica­ therapy withdrawn. Precise in­ years, were selected for the study tion; (xxi) psychotic disorders of structions were given that tablets after the objectives and implica­ any kind; (xxii) any specific con­ had to be taken at h 08.00 a.m. tions of the trial were explained traindication for any of the study and that magnesium-based anta­ to them, using the vernacular substances. cids could not be used during the where necessary to ensure that study. No medications other informed oral consent was ob­ Measurements than the trial formulations were tained. prescribed. One placebo tablet Twelve patients were Black Arterial pressures were mea­ was indicated to be ingested and nine were Caucasoid. All sured in the working arm by the daily for a 4-week baseline had morning resting supine dias­ standard indirect technique, period. After the end of the tolic blood pressures of using the first appearance and second week of this period, an­ 95-110 mm Hg (inclusive), re­ final disappearance of Korot­ other complete clinical evalua­ corded after 2 and 4 weeks of kofrs sounds to define systolic tion was performed, and an elec­ treatment with placebo. Patients and diastolic pressures respec­ trocardiogram, a chest X-ray and in whom comprehensive clinical tively. If sounds persisted to complete laboratory analyses - including ophthalmological 0 mm Hg, the point at which were carried out. -, laboratory electrical and ra- muffling occurred was taken as Patients with a supine diastolic diological investigations revealed the diastolic pressure reference. blood pressure of 95-110 mm one or more of the following, Patients rested · supine for Hg at the end of the second and were not included in the study: 10 minutes and erect for 3 min­ of the fourth week of the base­ (i) secondary hypertension of utes before measurement of the line period and who met none of any origin; (ii) malignant hyper­ corresponding blood pressures; the exclusion criteria proceeded tension; (iii) haemodynamically an average was obtained from to the active treatment phase of significant valvular heart dis­ three readings per patient in each the study. Patients were ran­ ease; (iv) congestive cardiac in­ bodily posture. The same mer­ domly and double-blind allo­ sufficiency; (v) left ventricular cury sphygmomanometer and cated to monotherapy with a insufficiency; (vi) right ventricu­ stethoscope were used through­ daily tablet of either HCTZ or lar insufficiency; (vii) sinus bra­ out the study and all clinical HCTZ +AMI. Arterial blood dycardia of less than 54.min- I evaluations and measurements pressure, pulse rate and body after 3 minutes supine rest; (viii) were made 2-4 h after the last weight were measured every 2 second or third degree atrio-ven­ intake of medication. weeks starting at the end of third tricular block; (ix) coronary in­ Serum Mg was measured by week of treatment. Plasma Mg, K sufficiency requiring pharmaco­ atomic absorption spectroscopy, and Na were measured every 2 logical treatment; (x) myocardial using a Yarian 275 instrument. weeks between the end of the infarction within the past six Serum Na and K were measured fifth and of the twenty-third months; (xi) a history or clinical by the ion-selective technique week of active treatment. A com­ evidence of cerebrovascular im­ using a Nova 4 analyser. All plete clinical evaluation, an elec­ pairment, including retinal hem­ other chemical analyses and hae­ trographic recording, a chest orrhages; (xii) renal dysfunction mato1ogical and urinary evalua­ X-ray and complete laboratory evidenced by proteinuria, by a tions were done by standard la­ measurements were carried out at serum creatinine level higher boratory methods. These deter­ the end of the twenty-third week than 1.5 mg.dL - I or by a blood minations included plasma glu­ of active treatment. urea higher than 60 mg.dL- I ; cose, creatinine, uric acid, urea, Compliance with treatment (xiii) clinically relevant hyper- or SGOT alkaline phosphatase and was assessed by counting the hypokalaemia; (xiv) a history or bilirubin, hemoglobin, hemato­ number of tablets returned at clinical evidence of gout; (xv) crit, white blood cell count, pia- each clinical visit. Magnesium-Bulletin 4/ 84 Leary et al. I Hydrochlorothiazide and amiloride combination on plasma magnesium 129

Statistics Results consecutive scheduled measure­ ments corresponding to the same Results are expressed as means Compliance with treatment patient, if existent, were aver­ and standard errors of means. was excellent in all cases. aged. Mean results are shown in Normality of frequency distri­ Nine patients received HCTZ Table II, where values measured butions and homoscedasticity of and twelve patients were treated 15 days apart - one or two val­ variances were evaluated by the with HCTZ+AMJ. ues per patient - have been as­ chi-square test for goodness of fit The systolic and diastolic cribed to the corresponding me­ and the F ratio respectively. Mi­ blood pressure mean values be­ dian-point in time. nor departures from formal pre­ fore and during treatment with requisites for parametric tests HCTZ and HCTZ+AMI are de­ Mean plasma magnesium con­ were tolerated. picted in Table I. The last meas­ centration fell significantly, with The t-test for dependent sam­ urement on placebo was taken as respect to pretreatment, after an ples was used for assessing the pretreatment (or untreated) average of 22 weeks of therapy significances of the differences blood pressure. Supine diastolic with either HCTZ or HCTZ + between any two mean values blood pressure showed mean val­ AMI. Individual mean plasma within the same active treatment ues below 95 mm Hg after 3 magnesium concentrations were group, and a t-test for independ­ weeks of treatment with all above 0.75 m mol. L -I after ent samples was used for eval­ HCTZ+ AMI and after 5 weeks 8-10 weeks of treatment with ei­ uating the significances of the of therapy with HCTZ, and re­ ther formulation. After a mean of differences between any two mained within the normal range 22 weeks of therapy, individual mean values corresponding to under either formulation for the plasma magnesi um concentra­ different active treatment groups. rest of the study. tions were below 0.75 mmol. L - I AJl statistical tests deployed Since plasma Mg, K and Na in eight out of the nine patients were two-tailed and p = 0.05 measurements were not carried taking HCTZ and in six out of was considered the limit of sig­ out in all patients at all sched­ ten of the patients taking nificance. uled instances, values from two HCTZ+AMI.

Table 1: Changes in blood pressure (mm Hg) induced by treatment of nine hypertensive patients with hydrochl orothiazide 50 mg (HCTZ) daily and of twelve hypertensive patients with a combination of hydrochlorothiazide 50 mg and amiloride 5 mg (HCTZ+ AMI) daily. Values as means ±S.E.M.

Duration of treatment (weeks) Treat- Blood Pre- ment pressure treat- 3 5 7 9 11 13 15 17 19 21 23 ment HCTZ Supine 156 147b 14()a*** 144** 143* 140**** 140* 141 *** 144•*** 136*** 139**** 146• systolic ±4 ±5 ±4 ±4 ±6 ±3 ±6 ±5 ±5 ±5 ± 4 ±8 Supine 98 96b 96• 94* 93** 91 *** 92*** 91*** 94** 90*** 91 ** 92• diastolic ±2 ± 2 ±3 ±2 ± 2 ±2 ±2 ±2 ±2 ±3 ±2 ±3 Erect 149 137b* 137•* 135*** 136** 132*** 129*** 132*** I 36•*** 132*** 133**** 142< systoli c ±5 ± 4 ±6 ±3 ±5 ± 4 ±5 ±6 ±4 ±6 ±5 ±7 Erect 100 92b 94• 92 92 89* 90 90 93• 89** 90 94• diastolic ±4 ± 2 ±3 ± 2 ± I ±3 ±2 ±2 ± 2 ±3 ±2 ±3 HCTZ Supine 146 137• 136 133* * 127*** 129** 129** 125*** 125*** 126d*** 132d* 13Jb* +AMI systolic ±3 ±6 ±5 ± 4 ±3 ± 4 ± 4 ± 4 ±4 ±3 ±6 ±6 Supine 100 93•*** 92**** 93* 90**** 90*** 89*** 86**** 87**** 85d**** 89d*** 84b*** diastolic ± I ±2 ±2 ±3 ±2 ±3 ±3 ±2 ±2 ±2 ±3 ±3 Erect 142 134• 131 * 130** 122**** 132 12 1*** 120*** 120*** 122d*** 127d* 126b*** systolic ± 3 ±5 ± 4 ±3 ±2 ±5 ± 4 ±3 ±4 ±3 ±5 ±6 Erect 97 93• 94 93 88*** 89*** 86*** 85*** 84*** 84d*** 88d*** 84b*** diastolic ±2 ±3 ±2 ±2 ± I ±2 ±3 ±2 ±2 ±2 ±3 ±3

results from eight patients. results from seven patients. results from six patients. results from eleven patients. results from nine patients. * p < 0.05 with respect to pretreatment mean value. ** p < 0.02 with respect to pretreatment mean value. *** p < 0.01 with respect to pretreatment mean value. **** p < 0.001 with respect to pretreatment mean value. 130 Leary et al. I Hydrochlorothiazide and amiloride combination on plasma magnesium Magnesium-Bulletin 4/ 84

Table 11: Changes in serum electrolyte concentrations (m mol. L 1) induced by treatment of nine hypertensive patients with hydro- chlorothiazide 50 mg (HCTZ) daily and of twelve other hypertensive patients with a combination of hydrochlorothiazide 50 mg and amiloride 5 mg (HCTZ+AMI) daily. Values as means ± S.E.M.

Serum Averaged duration of treatment (weeks) Treatment electrolyte Pre- concentration treatment 6 10 14 18 22

HCTZ Magnesium 0.77 ±0.03 0.8 1 ±0.03 0.80±0.01 0.80•±0.03 0.76h±0.02 0.70* ±0.01 (8) ( 17) (1 6) (15) (18) (15) Potassium 3.8±0.2 4.1 ±0.2 3.7±0.2 4.0±0.1 3.9 ± 0.1 4.1 ±0.1 (8) (17) (16) (15) ( 17) (15) Sodium 146± I 146 ± I 146 ± 0.0 145± I 146 ± I 144 ± I (7) (16) (16) (12) (15) ( 14) HCTZ Magnesium 0.82±0.02 0.87** ± 0.02 0.83±0.01 0.83c±O.OI 0.80 ± 0.02 0.74c** ± 0.02 +AMI (12) (23) (24) (15) (22) (15) Potassium 4.6 ±0.2 4.3±0.1 4.0**±0.1 4.0<±0.2 4.4±0.1 4.2<±0.2 (12) (23) (24) (1 5) (22) (15) Sodium 145± I 147 ± I 146±0.0 l45c± I 145± l )44c±) (12) (23) (24) (1 5) (22) (15)

Figures between brackets depict the number of measurements from which the corresponding statistics were derived. Va lues from two consecutive measurements performed 15 days apart in the same patient were averaged whenever existent, and average values were used for evaluating the corresponding statistics. results from eight patients. results from seven patients. results from ten patients. * p < 0.05 with respect to pretreatment mean value. ** p <0.01 with respect to pretreatment mean va lue.

Plasma potassium and sodium, tion, especiall y within the con­ Apparently, amiloride-hydro- pulse rate and the clinical and text of studies on the effects of chlorothiazide weight ratios instrumental variables s tudied diuretics on bodily Mg status [13, higher than 1:10 would be neces­ did not reveal any important 28,30]. sary for amiloride to completely changes during treatment. Both Hydrochlorothiazide provokes compensate for the hypermagne­ formulations were equally well renal retention of Ca [4] and thus si uretic e ffect of hydrochloro­ tolerated and no side-effects depresses parathyroid function thiazide, though these higher were reported or detected that [32] and decreases the parathor­ weight ratios could be hazardous merited withdrawal of any pa­ mone-dependent reabsorption of in terms of ami1oride potential tient from the study. Mg in the loop of Henle [ 19, 31 ], side-effects, especiall y acidosis Crossed comparisons between which is followed by hypermag­ and K intoxication. the plasma Mg, K and Na con­ nesiuresis [ 15]. In addition, hy­ Amiloride directly decreases centrations in the two groups did drochlorothiazide hypercalcae­ the amount of Mg in the end not yield any significant differ­ mia per se might reduce Mg portion of the distal convo­ ence, either before the initiation reabsorption in the loop of Henle luted tubule and in the early col­ of treatment or at any time du­ [22], thus further contributing to lecting duct, thus decreasing ring active therapy. the diuretic-induced hypermag­ magnesiuresis [ 17, 28]. Whether neslUresis. this effect is due to decreased Mg Discussion Amiloride reduces the renal secretion or to increased Mg output of Mg, in a dose-depend­ reabsorption remains to be eluci­ The antihypertensive actions ent manner, when single doses of dated. The direct action of ami­ exerted by HCTZ and by the drug are given to healthy vol­ loride on Mg handling at the HCTZ+AMI were consistent unteers [8, I 7]. This Mg-sparing end-distal tubule and at the with the results o f previous stud­ effect is however feeble and, early-collecting duct is opposed ies [26, 29]. when single standard-dose com­ by the ea-mediated indirect ef­ Plasma Mg does not correlate binations of amiloride and com­ fect of the drug on the handling linearly with tissue Mg. How­ mon diuretics are administered of Mg in the early distale tubule, ever, significant decreases - to normal subjects, the hyper­ which parallels that of common when existent - in plasma Mg magnesiuretic effects of common distal tubular diuretics in so far are usually taken as tardy, albeit diuretics are but partly counter­ as amiloride causes renal Ca re­ reliable, indicators of Mg deple- acted by amiloride [9, 10, 16]. tention [2, 3, 8, 12, 18, 20, 21 , 23]. Magnesium-Bulletin 4/84 Leary et al. I Hydrochlorothiazide and amiloride combination on plasma magnesium 131

The addition of the ea-retaining at high risk of developing Mg de­ diac failure. Mod. Geriat. 3 (1973) effects of amiloride and hydro­ ficiency [28], or therapeutically if 266-273. [13] Kohvakka, A., L. Heinonen, P. Pieti­ chlorothiazide could explain that plasma Mg falls below nen, H. Salo. A. Eisalo: Potassium HCTZ+ AMI in creases magnesi­ 0.75 mmoi.L- I [28]. and magnesium balance in thiazide uresis and lowers plasma Mg treated cardiac patients with special reference to diet. Acta Med. Scand., upon prolonged administration, References since the positive feed-back me­ Suppl. 668 ( 1982) 102-109. [I] Altura, B. M.: Magnesium and regu­ [ 14] Leary, W. P .. A. J. Reyes: Antihy­ chanisms accounting for thia­ lation of contractility of vascular pertensive and metabolic effects of a zide-induced hypermagnesi­ smooth muscle. Adv. Microc. 11 combination of hydrochlorothiazide uresis [24, 28] could be set to a (1982) 77-1 13. and amiloride. S. Afr. Med. J. 60 level unlikely to be counteracted [2] Ambrosioni, E., F. Tartagni, A. M. (198 1) 381-384. W. P., A. J. Reyes: The mag­ by the direct effect of amiloride Lusa, L. Bassein, B. Magnani: Ef­ [15] Leary, fects of tienilic acid used alone and nesiuric effect of a single dose of hy­ on the nephronal handling of in association with triamterene or drochlorothiazide in healthy adults. M g. amiloride on urinary excretion of Curr. Ther. Res. 32 (1982) 425-431. An alternative or complemen­ electrolytes. lnt. J. Clin. Pharmacol. [ 16] Leary, W. P., A. J. Reyes, K. van der tary explanation for the deleter­ Ther. Toxicol. 19 (1981) 445-449. By/: Effects of a combination of hy­ drochlorothiazide and amiloride on chronic treatment [3] Biadi, 0., C. Sighier, M. Mariani: ious effect of Comparison between two diuretic urinary magnesium excretion in with HCTZ +AMI on magnesae­ drugs: a double-blind clinical exper­ healthy adults. Curr. Ther. Res. 35 mia, could lie on the fact both imentation. Drugs Exp. Clin. Res. 7 ( 1984) 293-300. active principles in the formula­ (1981) 763-772. [ 17] Leary. W. P., A. J. Reyes, K. van der Urinary magnesium and zinc tion increase plasma aldosterone [4] Bloch, R., C. Steiner, M. Welsch, J. By/: Schwartz: L'effet hypocalciurique de excretions after two different single values. Hyperaldosteronaemia !'hydrochlorothiazide, de la chlor­ doses of a miloride in healthy adults. could increase magnesiuresis thalidone, de l'indapamide et de Curr. Ther. Res. 34 (1982) 205-216. [25] to an extent that would not l'acide tienilique. Therapie 36 (1981) [18] Lehr, D.: Magnesium and cardiac be overcome by the antagonistic 567-574. necrosis. Magnesium-Bull. 3 (1981) [5] Classen. H.-G.: Stress and magne­ 178-191. action of amiloride. sium. Artery 9 (198 1) 182-189. [19] Levine, B. S., J. W. Coburn: Magne­ Irrespective of the mechanisms [6] Dyckner, T .. P. 0. Wester: Effect of sium, the mimic/antagonist of cal­ accounting for the decrease in magnesium on blood pressure. Br. cium. N. Eng. J. Med. 310 (1984) plasma Mg provoked by Med.J.286(1983) 1847-1849. 1253-1255. [20] Marier, J. R.: Role of environmental HCTZ+AMI, which matched [7] Ebel, H., T. Gunther: Role of mag­ nesium in cardiac disease. J. Clin. magnesium in cardiovascular dis­ that provoked by HCTZ, the Chem. Clin. Biochem. 21 (1983) eases. Magnesium 1 (1982) present findings suggest that the 249-265. 266-276. deployment of HCTZ+ AMI [8] Hamdy, R. C., M. E. Vinson. A. D. [21] Maschio, G., N. Tessitore, A. D'An­ A. Fabris, F. Pagano, A. Tasca, should be discouraged whenever Robbins, L. P. L. Struthers, S. F. gelo. Chapman, R. J. Norris, H. L. Shaw: G. Graziani, A. Aroldi. M. Surian, G. a more innocuous alternative is Diuretic potency of loop, thiazide Colussi, A. Mandressi, A. Trinchieri, available. HCTZ+AMJ should and potassium sparing agents: a F. Rocco, C. Ponticelli, L. Minetti: be particularly avoided in pa­ reapprisa1 of relative activity. In : Prevention of calcium nephroli­ tients under stress and in areas Puschett, J. B. (ed.): Diuretics. El­ thiasis with low-dose thiazide, ami­ loride and allopurinol. Am. J. Med. where the Mg content in drink­ sevier, New York 1984, pp. 403-406. 71 (1981) 623-626. ing water is low, since these fac­ [9] Hamdy, R. C., M. E. Vinson, A. D. [22] Quamme. G. A.: Effect of hypercal­ tors predispose to the develop­ Robbins, L. P. L. Struthers, S. F. cemia on renal tubular handling of ment of Mg depletion [5, 11, 20]. Chapman, R. J. Norris, H. L. Shaw: calcium and magnesium. Canad. J. Low doses of diuretics (e.g. hy­ The short term effect of potassium Physiol. Pharmacol. 60 (1982) sparing diuretics combined with 1275-1280. drochlorothiazide 12.5 mg.day-1 loop and thiazide diuretics. In : Pus­ [23] Ravenscroft, P. J., G. R. Hall, J. T. or chlorthalidone 25 mg.day- l) chett, J. B. (ed.): Diuretics. Elsevier, Ahokas. B. T. Emmerson. J. A. Tob­ are sufficient for achieving maxi­ New York 1984, p. 370. ert: lndacrinone: modification of mal antihypertensive effects and [10] Hamdy, R. C., M. E. Vinson , A. D. diuretic, uricosuric, and kaliuretic Robbins, L. P. L. Struthers, S. F. actions by amiloride. Clin. Pharma­ are not as likely as standard di­ Chapman, R. J. Norris, H. L. Shaw: col. Ther. 28 ( 1980) 45-5 I. uretic doses to cause Mg deple­ 24 hour urinary electrolyte profile [24] Reyes, A. J.: Arritmias cardia cas tion [28, 33]. When higher doses following frusemide, amiloride and causadas por deficiencia de magne­ of diuretics are needed for the a combination of these drugs, Fru­ sio: complicaci6n principal del tra­ treatment of cardiac insuffi­ mil. ln: Puschett, J. B. (ed.): Diuret­ tamiento usual con diureticos. Pren. ics. E1sevier, New York 1984, pp. Med. Argent. 70 (1983) 448-456. ciency and/or oedema, HCTZ+ 364-366. [25] Reyes, A. J.: Correlations between AMI should be preferred to [1 1] Karppanen, H.: Epidemiological diuretic-induced increases in mag­ HCTZ because of its milder ef­ studies on the relationship between nesium and potassium urinary out­ fect on bodily K, though plasma magnesium intake and cardiovascu­ puts in normal subjects. Manuscript lar diseases. Artery 9 ( 1981) in preparation, 1984. Mg should be measured fre­ 190-199. [26] Reyes, A. J.: Efecto antihipertensivo quently and Mg supplements [12] Kennedy, R. D., J. P. R. MacFar­ de Ios diureticos. Rev. Hisp.-Am. given prophylactically to patients lane: Amiloride in congestive car- Hipert. Art. J (1983) 16-27. 132 Learyet al./ Hydrochlorothiazide and amiloride combination on plasma magnesium Magnesium-Bulletin 4/ 84

[27] Reyes, A. J., W. P. Leary: A formal ciated hypomagnesaemia. Br. Med. Nuo/lo, A. Keriinen: Effect of low method for the therapeutic classifi­ 1.285(1982) 1157-1159. dose diuretics on plasma and blood cation of antihypertensive diuretics. [31] Shils, M. E.: Magnesium, calcium cell electrolytes, plasma uric acid Curr. Ther. Res. 30 (1981) and parathyroid hormone interac­ and blood glucose. Acta Med. 1073-1088. tions. Ann. N.Y. Acad. Sci. 355 Scand., Suppl. 668 ( 1982) 95-10 I. [28] Reyes, A. J., W. P. Leary: Diuretics (1980) 165-180. [34] Wester. P. 0., T. Dyckner: Problems and magnesium. Magnesium-Bull. 6 [32] Singhellakis, P. N., A. E. Nikon, C. with potassium and magnesium in (1984) 87-99. Nicolon, D. Mauromatis, D. G. diuretic-treated patients. Acta Phar­ [29] Reyes, A. J., W. P. Leary: Mathe­ lkkos: Effect of a thiazide diuretic macol. Toxicol. 54 (Suppl. I) ( 1984) matical model of the antihyperten­ (bendroflumethiazide) on parathy­ 59-<56. sive effect of a combination of hy­ roid function in humans. Acta En­ drochlorothiazide and amiloride. docrinol., Suppl. 261 (1983) 32-35. Curr. Ther. Res. 30 ( 1981) 244-252. [33] Sundberg, S., H. Sa/o, A. Gordin, L. Address for reprints: Prof Dr. A. J. Reyes, [30] Sheehan, J., A. White: Diuretic-asso- Melarines. U. Lamminsiou, E. Holanda 1724, Montevideo, Uruguay