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.