Diuretics and Magnesium 87

Magnesium-Bulletin 3/84 Reyes et al. I Diuretics and magnesium 87 Diuretics and magnesium By A. J. Reyes and W. P. Leary Universidad de la ~epublica and Fundaci6ri, Procardias, Montevideo, Uruguay, and University of Natal, Durban, South Afnca . Zusammenfassung brovasculaires ainsi qu'au developpe The chronic administration of Die chronische Gabe von Diuretika ment d'arythmies cardiaques pendant common diuretics at standard mit Angriffspunkt an der Henleschen )'infarctus aigu du myocarde et aux alte· rations du metabolisme lipidique et gluci doses may give rise to diverse Schleife oder am distalen Tubulus kann cardiac arrhythmias, including zur Mg-Verarmung des KOrpers fiihren. dique qui ont lieu pendant le traitement Das resultierende Mg-Defizit destabili diuretique. La prevention de ces effets ventricular fibrillation, or sudden siert die elektrische Erregbarkeit des indesirables des diuretiques doit etre death, and may also increase the Myokards und ist Hauptursache fiir das effectuee par une selection adequate de risks of myocardial infarction la substance diuretique, !'usage de doses Auftreten von Arrhythmien nach and of arrhythmias complicating Behandlung mit Diuretika. Der Mg-Man minimales, !'ingestion optimale de Na et gel fordert die Entwicklung von Erkran de Mg et !'administration de Mg chez acute myocardial infarction [74, kungen der Coronar- und Cerebralge certain malades. 81]. fiiBe, das Auftreten von Arrhythmien Classically, K-deficiency wiihrend des akuten Myokardinfarktes caused by common diuretics has und StOrungen des Lipid- und Kohlenhy been incriminated as the princi- · dratstoffwechsels bei Therapie mit Diure Modem diuretics may be clas tika. Diese unerwiinschten Nebenwirkun sified it;tto three groups. Loop pal pathogenic factor of arrhyth gen kOnnen vermieden werden durch diuretics such as furosemide, mias provoked by these drugs Auswahl von Diuretika, die keine ethacrynic acid, bumetanide, [62, 65, 68]. However, K defi~ Mg-Verluste induzieren, durch Minimie ciency is only a contributing fac rung der Dosis, durch Optimierung der muzoliniine and piretanide have Na- und Mg-Ahfnahme und in eini their main site of renal action at tor, whereas the principal deter gen Fallen - durch Supplementierung a common acceptor in the thick minant of diuretic-induced car mitMg. ascending portion of the loop of diac arrhythmias is Mg defi Henle [74, 81]. The main sites of ciency, which is secondary to the renal action for distal tubular hypermagnesiuria induced by Summary diuretics, including thiazides, common diuretics [18-23, 74, The chronic administration of common chlorthalidone, chlorexolone, 82-85, 90, 95, 105-107]. In all loop or distal tubular diuretics may lead indapamide and xipamide, are at cases of cardiac arrhythmias un to somatic depletion of Mg. The resultant equivocally due to common deficiency of Mg destabilizes the myocar specific acceptors for each sub dium electrically and is the principal stance, in the first portion of the diuretics, in which appropriate cause of cardiac arrhythmias ascribed to 'distal convoluted tubule [74, 81]. laboratory analyses were carried diuretics. Mg deficiency positively contri The K-retaining diuretics out, Mg deficiency was identi butes to the development of coronary spironolactone, amiloride and fied as the causative factor and artery and cerebrovascular diseases, to the supplementation of Mg sup the occurrence of cardiac arrhythmias triamterene inhibit normal trans during acute myocardial infarction and to parietal interchange between pressed the arrhythmia, irrespec the derangements of lipid and carbohy N a, which is reabsorbed, and K tive of overall somatic K status drate metabolism that occur during treat· and H, which are excreted, in the [19, 23, 95]. ment with diuretics. These adverse effects final portion of the distal convo It possible that the well of diuretics can be avoided by selecting is diuretic formulations that do not cause luted tubule [74, 81]. known fact that .effective control Mg deficiency, minimization of the Common diuretics are defined of essential hypertension by diuretic dose, optimization of Na and Mg as those principally acting at the monotherapy with distal tubular intakes and, in some cases, supplementa diuretics does not reduce the tion of Mg. loop of Henle or at the distal convoluted tubule. A standard incidence of sudden death in diuretic dose of these drugs pro these patients could be explained by ,the deficiency of Mg which Resume vokes a natriuresis equivalent to that induced by 40 mg of. furo these drugs cause [83]. L'administration chronique des diureti ques usuels (diuretiques d'anse oti diure semide (loop diuretics) or to tiques distaux) peut conduire a une 50 mg of hydrochlorothiazide depletion somatique de Mg. Le deficit en Hypermagoesiul'ia and magnesium (distal tubular diuretics), when deficiency provoked by diuretics Mg altere electriquement le myocarde et these drugs are administered est la cause principale des arythmies c;r diaques imputees aux diuretiques. Le orally to healthy volunteers The effects on 24.hour urinary deficit en Mg contribue au developpe under controlled experimental Mg output of single standard ment des maladies coronariennes et cere- conditions [74]. doses of several common diuret- 88 Reyes et al. I Diuretics and magnesium Magnesium-Bulletin 3/84 N°0F %CHANGE IN 24-h MAGNESIURIA REFERENCE 1~~fS DRUG AND DOSE (mgl 0 20 40 60 80 100 N~ -0 N.S. 52 t 13 AMILORIDE 5 [I E -E 0,80 13 AMILORIDE 10 [] N.S. 52 j E ;:) j 7 CHLOREXOLONE 10 [:~:t~=~t:~:~:1:t~:1:i:i:tl p < 0.02 49 Ill Gl _N.S._ 9 CHLORTHALIDONE 100 E:~:~:~:~:;:;:;}:;:~:;:;:;:;:~:;:;:;:i:l:;:;:;:~t:~ p < 0.005 65 c 0,75 Ol rei __ N.S. __ 9 FUROSEMIDE 40 !:i:;:;:;:j:;:;:Iff~:i:j:l ·p < o.o5 84 E t 19 HYDROCHLOROTHIAZIDE 50 p < 0.05 51 E --- p<0,01 --- §Q ;:) '- 0,70 Gl 9 HYDROCHLOROTHIAZIDE 50 !t{:t;:;:;:~:i:i:itl p < 0.05 48 Ill 0 4 8 12 7 INDAPAMIDE 2,5 [] N.S. 86 weeks 10 MUZOLIMINE 30 D N.S. * Fig. 2: Changes in magnesaemia during the monotherapeutic treatment of nine ~ 13 XIPAMIDE 5 ~ p < 0.01 ** hypertensive patients with piretanide 12 mg/day. Mean ± S.E.M .. N.S.: non 13 XIPAMIDE 10 !{{:fi:~:;:;:~:;:;:;:;:;l p < 0.001 ** significant. From Leary and Reyes [ 46], by courtesy of South African Medical 13 XIPAMIDE 20 !ff~:j:j;j;jf:1:jl p < 0.001 ** Journal. 19 +HYDROCHLOROTHIAZIDE 50 r.::J AMILORIDE 5 t:!:J N.S. 51 Fig. 1 : Summary of the results from several studies in which healthy volunteers were the distal convoluted tubule given single doses of diuretic formulations. Th~ bars depict percentual changes in [69-71]. Parathormone pro 24-hour urinary Mg output after thes~ diuretics with respect to control 24-hour magne motes Mg reabsorption at the siuria. N.S.: non significant. *Leary, W~ P., Reyes, A J., van der Byl, K.: ·curr. Ther. Res., in press. **Reyes, A. J., Leary, W. P.: manuscript in preparation. · loop of Henle and, perhaps, at the distal convoluted tubule [56, 66, 71]. The kidney, which is the ics were studied in normal, bio measured before and during principal regulatory organ of Mg logically equivalent, volunteers treatment with the loop diuretic. metabolism, handles this cation under controlled conditions. piretanide 12 mg/day in nine independently from Cl, Na and Chlorexolone, chlorthalidone, patients, the variable was found. K [56, 66, 69-71]. furosemide, hydrochlorothiazide to be significantly decreased and xipamide induced signifi after twelve weeks of therapy Loop diuretics cant hypermagnesiuria in the [46] (Fig. 2). Hydrochlorothia 24-hour period after dosing with zide 50 mg (9 patients) or a Qom Loop diuretics block the trans active medication (Fig. 1). The bination of hydrochlorothiazide parietal reabsorption of Mg at loop diuretic muzolimine 30 mg, 50 mg and amiloride 5 mg the thick ascending portion of the distal convoluted tubular (12 patients) reduced plasma Mg the loop of Henle [69, 71]. This diuretic indapamide 2.5 mg and significantly in hypertensive blockade is independent from the K-retaining diuretic amilor patients given these diuretics as that of Cl reabsorption at the · ide 5 or 10 mg did not affect uri monotherapy after an average of same anatomical level, which nary Mg output significantly 20 weeks (Leary, W. P., Reyes, a'ccounts for the natriuretic effect (Fig. 1). The combination of A. J., van der Byl, K.: unpub of loop diuretics [56, 71 ]. After hydrochlorothiazide 50 mg and lished). the administration of placebo to amiloride 5 mg also had no effect normal volunteers, the mean Cl, on 24-hour magnesiuria (Fig. 1). Na, fluid and Mg urinary flow All tested formulations signifi Mechanism of magne$ium curves, derived from experimen- cantly increased 24-hour urinary deficiency provoked by diuretics . tal data according to the Reyes Na output and chlorexolone, and Leary mathematical model chlorthalidone, hydrochlorothia Normal urinary Mg output [78], indicate that the time zide, indapamide, muzolimine ranges from 4 to 8 mmoll day courses of all these urinary excre and xipamide increased 24-hour (100-400 mg/day). Most fil tions are parallel (Fig. 3). After urinary.K output significantly. tered Mg is reabsorbed in the the administration of a loop No data exist on the effects nephron, 20-30 o/o at the proxi diuretic to the same probands, chronic administration of diuret mal convoluted tubule, 50-60 o/o urinary Mg flow is delayed With ics has on total bodily Mg. In a at the thick ascending portion of respect of those of Clj Na and study where plasma Mg was the loop of Henle and 1-5 o/o at fluid [84] (Fig. 4). This fact sug- Magnesium-Bulletin 3/84 Reyes et al. I Diuretics and magnesium 89 common drstal tubular diuretic loop dl"'etio \- 1-distal Mg reabsorption calciuria /Mg reabsorp7ionin ~ + ( )_ Henle's-loop_ l calcaemia man)esiuria I ~ ~ + G + )/';nal:ffed of PTHS-_ )_ 24 serum PTH -magnesaemia hours Fig.

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