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. 3: Mean urinary Na and Mg flows after the administration of placebo per os ,jittnal a~on):ffed of PTH of Ca to nine healthy volunteers at time 0 of the experiment (08.00). The time courses of natriuria and magnesiuria are similar; Fig. 5: Causal diagram of the determination of Mg deficiency provoked by loop and their peaks therefore practically coincide distal tubular diuretics. The diagram depicts changes ( + : augmentation; - : diminu in time. From Reyes and Leary [85}, by tion) resulting from increases in the variables at which arrows start (system dynamics courtesy of Current Therapeutic notation). PTH: parathyroid hormone. From Reyes [73], by courtesy of La Prensa Research. Medica Argentina.

~ FUR o 40 excretion in this manner, and to it limit Mg and ea mobiliza E perpetuating hypermagnesiuria tion from its main store, thus 20l : ~~=> [82]. Mg deficiency ensues reinforcing hypocalcaemia, 0 :, unless its exogenous supply is which diminishes magnesiuria ..... 0 .1--....---=====:, increased. Mg· deficiency reveals directly, i.e. independently from .!!! itself as hypomagnesaemia only PTH [70, 71]; this compensating 3 4 E 0. 1 8-15 weeks after the initiation mechanism is however of limited ~ .2 of diuretic treatment [46} quantitative importance. The 0 2 ~· * · because of Mg mobilization from decreases in sPTH and in its ·~ gE 0 -r------. bone to plasma (82]. renal effect decrease the activity ~ ,... Mg deficiency decreases the of renal 1-hydroxylase; the syn 0 3 4 2 release of PTH since the cation thesis of 1,25 (OH2) D3 is there hours normally activates parathyroid fore decreased and hypocalcae Fig. 4: Mean urinary Na and Mg flows adenylate cyclase by competition mia aggravated. Hypocalcaemia after the administration of furosemide 40 with ea at the modulating site of stimulates the activity of renal mg per os to nine healthy volunteers at the enzyme or by promotion of 1-hydroxylase and consequently time 0 of the experiment (08.00). The time course of magnesiuria is delayed with res the synthesis of endogenous the synthesis of 1,25 (OH2) D3; pect to that of natriuria. From Reyes and guanine nucleotides [54]. In hypocalcaemia and hypomagne Leary [84], by courtesy of Current Thera addition, Mg deficiency causes saemia are thus partially com peutic Research. resistance to the action of PTH pensated · for~ however, this in bone and in the kidney [27, mechanism has no quantitative 28, 92), apparently because it significance. gests that a slow mechanism con· obtunds interaction between the Although muzolimine 30 mg tributes to the hypermagnesiuria hormone's receptor and adeny did not increase 24-hour urinary induced by loop diuretics, in late cyclase, an enzyme which is Mg output significantly (Fig. 1), addition to the direct blockade of positively influenced by PTH it delayed urinary Mg flow with . the reabsorption of the cation [99]. Thus, Mg deficiency respect to Na in the same man [82]. decreases sPTH and increases ner as furosemide 40 mg (Leary, Loop diuretics provoke hyper renal and bone resistance to it; W. P., Reyes, A. J., van der Byl, calciuria [81, 87] which de~eases both these facts tend to increase K.: eurr:. Ther. Res., in press). calcaemia and thus increases hypermagnesiurla (Fig. 5). More This indicates that muzoUmine, serum (s) parathormone (PTH) over, furosemide has been found at its standard diuretic dose. [24]. PTH mobilizes ea and Mg to directly diminish renal sensi brings into. play the mechanisms from bone, increasing the tivity to PTH [102]. The diminu that account for loop-diuretic amount of Mg available for renal tion in sPTH and bone resistance induced hypermagnesiuria. The 90 Reyes et al. I Diuretics and magnesium Magnesium-Bulletin 3/84

possibility that this formulation further increasing magnesiuria. Treatment with common could provoke significant deple The subsequent mechanisms diuretics may significantly di tion of somatic Mg upon pro whereby distal convoluted tubu minish the intramyocardial con longed administration should lar diuretics provoke hypermag tent of Mg [23, 64, 95, 107]~ This therefore be evaluated. Higher nesiuria are similar to those asso decreases the activity of the N a+, doses of this substance could be ciated with loop diuretics K+-ATPase which accounts for expected to induce hypermagne (Fig. 5). the generation of energy used for siuria acutely. Indapamide 2.5 mg probably the active transport of K into the did not provoke hypermagnesi cell and of Na from it (Na-K uria because the dose adminis pump), since Na+, K+-ATPase Distal convoluted tubular diuretics tered, which exhibits the maxi requires Mg as a cofactor [23, mal antihypertensive effect of 67]. In consequence, the intra Hypermagnesiuria provoked this subst~nce [76], is well below myocardial concentration of N a by diuretics acting at the distal its standard diuretic dose. How increases and that of K decreases convoluted tubule cannot be ever, after indapamide 2.5 mg when Mg deficiency is present explained solely by direct block there was a delay in urinary Mg (Fig. 7). The reduction in the ade of the transparietal reabsorp flow with respect to that of Na intracellular concentration of K tion of the cation since only [86], which suggests that this is aggravated by somatic K expo 1-5 % of filtered Mg is reab oiuretic provokes hypermagnesi liation which results from the sorbed in the distal tubule. In uria at higher doses. hyperkaliuresis provoked by experiments similar to those des common diuretics [46, 48, 49, 61, cribed for furosemide, significant Potassium-retaining diuretics 62, 79, 81, 84--86]. Diuretics dephasing was found between increase the amount of Na reach the time courses of urinary Mg The K-retaining diuretic ami loride reduced urinary Mg excre ing the final portion of the distal and urinary Cl, N a and fluid convoluted tubule and therefore after the administration ,of tion, although this reduction was statistically not significant, and it the normal interchange between diuretics such as hydrochloro N a and K, H is increased. In thiazide [48] (Fig. 6), chlorthali did not alter the time course of Mg urinary flow in normal indi addition, hyponatraemia and the done, xipamide (Reyes, · A. J., relative decrease in heart output, Leary, W. P.: unpublished) and viduals [52]. When a combina tion of amiloride 5 mg and elicited by the natriuretic action chlorexolone [49]. of diuretics, increase aldosteron These diuretics cause hypocal hydrochlorothiazide 50 mg was administered to healthy volun aemia which further elevates the ciuria [11], followed by hypercal• N a - K, H interchange in the caemia, which increases magne teers there was also no signifi cant change in Mg output [51] distal convoluted tubule [37, 81, siuria [70] and reduces sPTH I 00]. In familial hypokalaemic [70]. The decrease in sPTH (Fig. 1). This suggests that ami loride induces Mg reabsorption alkalosis with tubulopathy [35] diminishes the reabsorption of hypermagnesiuria occurs in asso Mg in the loop of Henle, thus and therefore acts as a Mg~sparer when the amount of the cation ciation with hyperaldosteronae~ mia and hypomagnesaemia '-.c..... passing through the distal convo 0 40 HCTZ luted tubule is increased by the increases aldosteronaemia inde E pendently from the renin-angio E action of common diuretics at ~ 20l more proximal nephronal sites. tensin system, but it is unlikely ~ that these mechanisms operate 0 ~ 0 ~ This effect of the amiloride and ;: . hydrochlorothiazide combination during the treatment of ordinary ill patients with common diuret ::> only occurs upon acute adminis -0 tration; its prolonged administra ics [56]. The increase in proton Ill E ~l tion causes hypomagnesaemia excretion in urine elevates extra >. 0.1 .... l ~I (Leary, W. P., Reyes, A. J., van cellular pH, thus facilitating the "'c entrance of K into the cell by dif . ·c "' 0 derBy/, K.: unpublished) . :::l E fusion; however, the factors that 0 6 24 decrease intracellular K (in Pathogenesis of cardiac hours creased kaliuresis, increased con arrhythmlas provoked by common centration gradient between the Fig. 6: Mean urinary Na and Mg flows diuretics after the administration of hydrochloro cell and the milieu interieur and thiazide 50 mg per os to nine healthy vol The following description has decrease in the Na+, K+-ATPase unteers at time 0 of the experiment its point of departure at the activity) predominate. (08.00). The time course of magnesiuria is retarded with respect to that of natriuria. electrically "resting" myocardial From Leary and Reyes [48], by courtesy cell. The processes described are Cytosolic Ca concentration of Current Therapeutic Research. summarized in Figs. 7 and 8. within the myocardium increases Magnesium.Bulletin 3/84 Reyes et al. I Diuretics and magnesium 91

K-retaining, Mg-sparing diuretic during· Mg deficiency [ l 05]. The urinary K increase in cytosolic Na secon dary to reduced Na-K pump +(+serum pH~ _ -( activity causes the transmito chondrial interchange of Na and d~stat Na-K,Hl~terchange . common /.+ ur~n(arJy Mg ea to rise so that Na passes into the mitochondria and ea from . . J . diuretic at 1stal Na avallapllity~--+.,...- standard . . · - them into the cytosol. The fall in +~ diuretic dose + serum Mg intracellular Mg concentration ( decreases the activity of the aldosteronaemia . 7 -( )+ Mg-dependent ea-ATPase that +( ~ ,/Na ~ntake//111.tracellular Mg accounts for the active transport serum K serum-Na + Mg rntakr;e+ )+ of ea from the cytosol into the endoplasmic reticulum, thus aug +/~ )- -( ~Ca-ATPase K intake/ I . 1 . . ·,: , ~ / . _...,activity menting cytosolic ea. Further + + + cytosottc ea~ 1 more, the decrease in intracellu intracellular K cytosolic Na -( ) J+ lar Mg leads to a net increase in +( ) . r.·'J -(· J . + . c:ticuloendoplasmic mrtochondnal ea inflow across the sarco - - + Ca 7! lemma, thus further elevating the Na,K-ATPase activity + V- + mitochondrial Na - cytosolic concentration of ea [2]. The falls in Mg and K concentra Fig. 7: Causal diagrams of the principal mechanisms whereby diuretics alter the tions and the increases in cyto intramyocardial concentrations of Mg, K, Ca and Na. The possibilities of several pro· solic Na and ea within the phylactic and therapeutic interventions are also shown. The diagram depicts changes myocardium are the prime fac ( +: augmentation; -: diminution) resulting from increases in the variables from tors underlying the occurrence of where arrows depart (system dynamics notation). From Reyes [73], by courtesy of La Prensa Medica Argentina. cardiac arrhythmias during treatment with common diuretics given that all these ionic de rangements destabilize the sarco lemma electrically, increasing myocardial excitability. Further mechanisms exist which are not as important as those already described but con tribute to the intramyocardial electrolyte disturbances pro voked by diuretics (Fig; 8). The haemodynamic effect of diuretics increases the secretion of catecholamines by the adrenals. The decrease in intracellular Mg and the increase in cytosolic Ca reinforce this secretion and also augment the release of catecho· lamines by the sympathetic nerve endings [3, 4, 6]. eatecholamines activate adenylate cyclase and promote the synthesis of cyclic adenosine monophosphate (cAMP) from adenosine tryphos phate (ATP). The increased adenylate cyclase activity is .rein forced because catecholamines decrease the secretion of insulin, which normally ·inhibits the Fig. 8: Causal diagram of the complement~ mechanismswhereby diuretics alter the intramyocardial concentrations of· Mg, .K, Ca ·and N a. The diagram depicts changes activity of the enzyme. A (+:augmentation; -: diminution) resulting ftom increases in the variables at which decrease in intracellular Mg arrows depart (system dynamics notation). s: serum; FFA: free fatty acids. From Re yes would cause a fall in the activity [73], by courtesy of La Prensa Medica Argentina. of adenylate cyclase, since Mg 92 Reyes et al. I Diuretics and magnesium Magnesium-Bulletin 3/84 promotes the activity of the sequently, the intramyocardial muli and attenuates vasodilata enzyme directly and is a cofactor concentrations of Ca [3] and Na tion induced by prostaglandins for . enzymes involved in the rise and those of Mg and K fall. or isoproterenol [2]. Mg and ver cyclation of guanosine nucleo- This is aggravated because pro apamil block the same ea-en tide which precedes the activa- tein synthesis is altered in Mg trance channel to the vascular tion of adenylate cyclase [67]; deficiency, since the cation acts smooth muscle cell [103]. The however, the overall effect .of the as a cofactor for enzymes administration of Mg accelerates various factors involved is a net involved in transcription and the rate of myocardial recovery increase in the activity of adeny- because the fall in intracellular K from ischaemia in experimental late cyclase [25]. The increase, in also affects protein synthesis. aJJimals [10]. cAMP availability is promoted Experimental Mg deficiency by diuretics like hydrochlorothia- Diuretics, magnesium deficiency induces characteristic structural zide [31] that inhibit the activity and coronary and cerebrovascular alterations in the myocardium of phosphodiesterase, the diseases [36] and in skeletal muscle [88]. enzyme which catalyses cAMP. Magnesium deficiency has In myocardial fibres, there is The amount of cAMP produced been identified as a coronary risk enlargement of the interstitial depends on ATP availability. factor. space of the transverse tubular Catecholamines reduce tissue The incidence of coronary system, a substance, possibly cal p02 and thus decrease the heart disease varies widely cium phosphate, precipitates in amount of ATP synthesized; between geographical regions vesicles of the longitudinal sys however, increased glycolysis and serious epidemiological stu tem of the endoplasmic reticu and lipolysis secondary to the dies have been carried out in lum and mitochondrial oedema rise in cAMP (Fig. 8) provide order to identify variables that with loss of mitochondrial matrix ATP via the production of free could explain these differences. occurs. The interstitial space is fatty acids (FFA). In Finland [44, 53] and in South enlarged, filaments and fibres of An increase in ATP tends to Africa [50] it was found that the isolated collagen are seen in the diminish glycolysis since it incidence of death ascribed to vicinity of the interstitial capil reduces the activity of phospho- ischaemic heart disease is laries and the fibrocyte endo fructokinase, which catalyses the ·inversely correlated with the con plasmic reticulum is increased rate limiting step of the glycoly- centration of Mg in drinking [36]. tic chain. However, glycolysis is water. The level of Mg in drink Stress increases catecholamine stimulated by the cAMP-depend- ing water ranges from 0.5 to 30 release and therefore induces Mg ent activation of the glycogeno- mg/ 1 in different regions and is deficiency, which further aug lytic enzyme phosphatase and taken as an index of the Mg con ments catecholamine levels [13]. also because the decrease in tent of foods produced in the Stress has been experimentally intracellular Mg activates phos- same geological area. Post mor found to provoke hypermagnesi- · phoenol pyruvate carboxykinase, tern studies in England have uria [5] and stressing factors, like an enzyme that catalyses glyco- demonstrated significantly noise, deplete somatic Mg stores neogenesis [59]. FFA bind ioni~ reduced intramyocardial and cor [13, 41]. Type-A behaviour [5], Mg in plasma thus removing it onary arterial wall Mg levels in stress [13], catecholamines [13] from the pool of ionic Mg which road accident victims who lived and alterations in plasma lipids is transferable to the cell [30]. in areas with Mg-deficient water [72] potentiate each other as fac This perpetuates and aggravates supplies [16]. tors determining Mg deficiency the intracellular Mg deficiency Plasma Mg concentration is and this interplay could explain provoked by diuretics. sigJJificantly lower in patients the high incidence of coronary Increased cAMP decreases the with moderately severe coronary heart disease in the population activity of lipoprotein lipase, heart disease, diagnosed by arter with type-A behaviour. thus reducing FFA liberation. iography, than in subjects with When diuretics are adminis Raised FFA levels decrease the mild or absent radiographic tered to persons under stress or activity of N a+, K +-A TPase, fur- changes [55]. with coronary heart disease, ther altering the intramyocardial Experimentally, Mg deficiency particular care should be exer electrolyte balance [83]. cAMP increases coronary [2-4, 96, 101- cised to prevent the development also activates cellular protein 103] and cerebrovascular tone [6, of Mg deficiency. kinase, which promotes the phos- 7] whereas Mg supplementation phorylation of sarcolemmal pro- has a corrective effect. Mg defi Diuretics, magnesium deficiency teins; the cell membrane perm ea- ciency increases vascular reactiv and hypertension bility to Ca, Na and K and Mg is . ity to catecholamines, angioten thus increased in favour of their sins, K, serotonin, vasospastic The possibility that Mg defi electrochemical gradients. Con- peptides and neurohumoral sti- ciency could ·contribute to the Magnesium-Bulletin 3/84 Reyes et al. I Diuretics and magnesium 93 development of arterial hyper Diuretic treatment, alterations in chloride tablets (Davis, W. H., tension has been postulated on lipid and carbohydrate metabo Warren, A.: personal communi the basis of indirect experimental lisms and magnesium deficiency cation; Reyes, A. J., Acosta•Bar• evidence [3]. However, no ade rios, T. N., Leary, W. P.: unpub quate epidemiological studies on Common loop and distal tubu lished). the relationship between the lar diuretics generally provoke incidence of hypertension and significant alterations in plasma Magnesium deficiency provoked dietary Mg content exist [58]. lipids, when they are adminis by diuretics clinical In a study of hypertensive tered at standard diuretic doses patients chronically treated with to normal volunteers or hyper It is difficult to diagnose Mg diuretics and with stable blood tensive patients for more than 4 deficiency in its early stages [15, press.ure values, it was found that weeks. The changes consist of 20, 25, 27, 29, 39, 91, 93]. Its subjects. presented hypomagne increases in total cholesterol [8, existence should be suspected saemia; oral •. Mg supplementa 26, 32, 35, 43, 46, 60J and/ or tri when diuretic treatment in stan tion in these' patients produced glycerides [8, 26, 35, 43, 45, 87] dard doses has been prolonged, both an increase in magnesaemia and of increases of the beta/ especially if any other factor and a significant reduction in alpha lipoprotein (LDL/HDL) exists that may precipitate or blood pressure [18]. This sug ratio [32-34]. The alterations in aggravate diuretic-induced Mg gests that the antihypertensive plasma lipids are generally con deficiency or cause Mg defi~ effect of diuretics may be ham sidered to increase the risk of cien6y per se (Table 1). Many of pered by the decrease in somatic cardiovascular disease. It is pos these factors may also provoke K Mg which these substances sible that Mg depletion is one of deficiency, which frequently induce. Plasma Mg concentra the factors leading to diuretic coexists with Mg deficiency in tion must be measured in hyper induced dyslipaemias [80], since patients treated with diuretics. tensive patients treated, with similar derangements of lipid Clinical manifestations of Mg common diuretics, and oral Mg ·metabolism occur in experimen deficiency include anorexia, nau supplements should be pre tal Mg deficiency when animals sea, apathy, muscular weakness, scribed in cases of hypomagne are fed a high lipid or carbohy fatigue, excitation and, in some saemia before considering the drate diet. Most investigations of cases, delirium or coma. Other effect of a diuretic maximal and the effects which diuretics have clinical signs are tetany, peri adding another antihypertensive on lipid metabolism [8, 12, 26, pheral tremor involving muscles to the therapeutic regime. 32-35, 43, 46, 60, 89, 104] have of the tongue, face and limbs, been biased by improper control ataxia, vertigo, lateral and verti- of diet or failure to take other cal nystagmus, tetany and con factors, such as· familial history vulsions. Occasionally positive Diuretics, magnesium deficiency of diabetes or dyslipaemia, into . Chvostek and Trousseau sign:s, and acute myocardial infarction account. Some of the effects of myoclonia or spontaneous car diuretics on lipid metabolism popedal spasms occur. Ad The myocardial content of Mg may be explained by the increase vanced Mg deficiency may be has been found to be low in nec in catecholamines elicited by confused with hypocalcaemia. .../ rotic and perinecrotic zones [14], these drugs (Fig. 8); other effects The most frequent cardiac both in necropsy specimens and could be related to the alteration arrhythmia is atrial fibrillation, after coronary artery ligation in in protein synthesis provoked by followed by ventricular and several species. ·Ventricular diuretics through increased K supraventricular extrasystoles arrhythmias occurring during and Mg excretion (Fig. 8). [95] and ventricular fibrillation. acute myocardial infarction re Both diuretics [31] and Mg The electrocardiographic signs of spond better to Mg than to other deficiency reduce glucose toler Mg deficiency are nonspecific antiarrhythmic agents [14, 63, ance thus causing a pathophy prolongation of the PQ, QTc and 90]. Consequently, an appro siological picture that resembles QUe intervals and flattening of priate therapeutic regime for diabetes mellitus, a condition the T waves [ 17]. Muscular de patients treated with common that is usually accompained by rangements of the inferior por diuretics who develop myocar depletion in bodily Mg stores tion of the oesophagous may lead dial infarction, or to whom and that may be aggravated by to dysphagia. diuretics are administered during diuretics or by Mg deficiency of Microcytic anaemia with the acute phase of myocardial any origin [42]. Patients with decreased erythrocytic half life, infarction, should usually dyslipaemias induced by diuret reticulocytosis and spherocytosis include supplementary Mg ics have been shown to respond may be present in blood. administered orally or parenter favourably to supplementation Hypocalcaemia and hypoka-. ally. of the diet with magnesium laemia resistant to supplementa- 94 Reyes et al. I Diuretics and magnesium Magnesium· Bulletin 3/84

Table I: Conditions that may provoke tion therapy have been reported Prophylaxis and treatment of magnesium deficiency per se or may pre in association with Mg defi magnesium deficiency and cipitate or aggravate magnesium defi ciency during diuretic treatment. Adapted ciency and metabolic alkalosis associated metabolic from Reyes [73], by courtesy of La Prensa also occurs. Total plasma lipids derangements during diuretic Medica Argentina. may be elevated [15, 20, 25, 27, treatment 29, 39, 92, 93]. No routine procedure exists Selection ofthe diuretic for the evaluation of total bodily formulation I. Conditions in which Mg supply Mg levels. Measurement of the to the milieu interieur is plasma Mg concentration is the The results of the experimental decreased. procedure of choice for diagnos series summarized in Fig. l and 1.1. Inadequate intake. ing Mg deficiency, although data from literature identify 1.1.1. Low Mg content in all foods. 1.1.2. Diet poor in Mg. experimental error is such that those currently available ,diuretic 1.1.3. Decreased food intake. atomic absorption spectrometry formulations which are unlikely 1.1.4. Parenteral nutrition with low Mg is the only acceptable method to provoke Mg deficiency. content. routinely available at the When a loop diuretic is chosen 1.2. Altered absorption. 1.2.1. Malabsorption syndromes. moment. Atomic spectrometry for prolonged treatment, muzoli 1.2.1.1. Gluten enteropathy. measures total plasma Mg; diffu mine 30 mg should usually be 1.2.1.2. Pancreatic insufficiency with sible Mg may be evaluated, in selected in preference to furo steatorrhoea. · plasma and tissues, by means of semide 40 mg which has been 1.2.1.3. Tropical sprue. a selective electrode [40], which found to induce Mg deficiency 1.2.1.4. Other. 1.2.2. Extensive enteral resection. is not yet used in the clinical and cardiac arrhythmias when it 1.2.3. Biliary and enteric fistuli. laboratory. is administered chronically [95]. 1.2.4. Excessive intake of oxalate and When the total plasma Mg When an antihypertensive phytate. concentration, referred to as diuretic is·needed, selection from 2. Conditions in which Mg lpsses are increased. magnesaemia, is less than 0.75 the formulations tested so far 2.1. Enteric. mmolll (1.50 mEq/1) Mg defi should be limited to indapamide 2.1.1. Vomiting. ciency is conventionally diag 2.5 mg or the combination of 2.1.2. Diarrhoea. nosed [20, 92]. The upper limit of hydrochlorothiazide 50 mg + 2.1.3. Repetitive gastric aspiration. normality is 1.05 mmolll (2.10 amiloride 5 mg. Indapamide 2.2. Excessive sweating. 2.3. Renal. mEq/1). It must be stressed that a 2.5 mg provokes hyperkaliuresis 2.3.1. Renal insufficiency with hyper normal plasma Mg level does not but in telemetric studies it has magnesiuria. necessarily exclude somatic Mg not been found to induce cardiac 2.3.2. Osmotic diuresis (glucose, manni- deficiency, since in the early arrhythmias during chronic tol, urea). · 2.3.3. Alcohol. stages of the condition Mg is administration [38]. Moreover, 2.3.4. Drug-induced hypermagnesiuria. mobilized from bone retarding indapamide 2.5 mg does not alter 2.3.4. I. Antineoplastics: cisplatin. any fall in Mg concentration. lipid [104] or carbohydrate [91] 2.3.4.2. Antibiotics: amphotericin B, car The concentration of Mg in metabolism. The hydrochloro benecillin, gentamicin, ticarcillin. striated muscle has been used to thiazide-amiloride combination 2.3.4.3. Cardiac glycosides. 2.3.5. Chronic parenteral nutrition with evaluate the ion content in soft does not provoke hyperkaliuresis · liquids. tissue [23 ], but it bears no linear or hypermagnesiuresis when 2.3.6. Renal tubular acidosis. relationship to myocardial Mg, administered acutely and does 2.3.7. Diuretic phase of acute tubular since the cation is retained in the not decrease striated muscle Mg necrosis. 2.3.8. Postobstructive polyuria. myocardium more readily than upon prolonged administration 2.3.9. Essential familial hypermagnesi in skeletal muscle. Lymphocytes [109]. However, mean serum Mg uria. provide an adequate means for level fell significantly by the 2.3.10. Essential sporadic hypermagnesi- estimating somatic Mg status, twentieth week of a study in uria. ( because they are metabolically which this formulation was given 3. Conditions in which various factors coexist. active, can be studied repeat as monotherapy to twelve 3.1. Hungry bone syndrome. edely [94] and intralymphocytic patients with essential hyperten 3.2. Hyperparathyroidism. and intramyocardial Mg contents sion (Leary, W. P., Reyes, A. J., 3.3. Hyperthyroidism. correlate linearly. van der By/, K.: unpublished). 3.4. · Excessive lactation. 3.5. Protein malnutrition. This preparation also alters lipid 3.6. Diabetes mellitus. and carbohydrate metabolism 3.7. Phosphate deficiency. [45]. 3.8. Metabolic acidosis. Diuretic formulations that 3.9. Primary hyperaldosteronism. cause important acute hypermag 3.10. Hypercalcaemia of any origin. 3.11. Acute pancreatitis. nesiuria, such .as chlorthalidone 3.12. Third term pregnancy. l 00 mg and xipamide 10 and Magnesium-Bulletin 3/84 Reyes et al. I Diuretics and magnesium 95

20 mg (Fig. 1) should not be essential hypertension. At these concentrations of skeletal and prescribed. doses hypermagnesiuria and cardiac muscles, it its likely that hyperkaliuria are minimized, these tissues respond similarly· to while the rate at which blood Mg repletion and that the sup Minimization ofdiuretic dose pressure falls and the final stable pression of arrhythmias by Mg is Minimization of diuretic dose value achieved are similar to due to a reactivation of Na +, is the most effective manoeuvre those recorded in response to K+-ATPase. Decreases in for reducing renal excretions of standard diuretic doses of the myocardial Mg and K concentra Mg and K and the deleterious same substances [75]. tions are not only caused by the effects of diuretics on lipid and administration of diuretics; digi carbohydrate metabolisms [74, talis inhibits myocardial Na +, 108]. K+-ATPase [1] and myocardial Diuretics are commonly pres ischaemia has a similar effect on Administration ofmagnesium cribed for patients with oedema intracellular electrolytes which or hypertension. Oedema should It is important' to .ensure a diet might contribute to the develop be treated initially by appro rich .in Mg in patients subjected ment of the arrhythmias com priate attempts at reversal of the to chronic diuretic therapy. Diets monly associated with myocar primary cause, optimization' of with at least 300 mg/day are dial infarction [23]. In these cir dietary salt intake and adminis recommended for adult women, cumstances Mg infusion has an tration of diuretics at standard 350 mg/ day for adult men and antiarrhythmic effect; animal doses. Double doses are required 450 mg/day during pregnancy. It studies have shown that this at the beginning of treatment if has been postulated that these measure nsults in repletion of ascites, which impairs the values should be higher, e. g. intracellular K and Mg ions in absorption of diuretics, is pres 450-470mg/day in adult men the infarcted area [23]. ent. When pl;"olonged diuresis is [66]. Growing children and per Intravenous Mg sulphate can necessary, the initial dose should sons under stress or with active be administered as an. immediate be reduced to the minimum com anabolism should receive at least measure in the treatment of ven patible with therapeutic objec 5 mg Mg/kg/day. Fruit, vegeta tricular arrhythmias associated tives, thus limiting urinary potas~ bles, dairy products and meat with diuresis, acute myocardial sium and Mg losses. This contain less than 30 mg of Mg infarction or digitalis ·therapy maintenance dose must be indi- · per 100 g, ,raw flours lOO and [20, 23, 95, 98]. The solution can vidually titrated but usually lies bananas 200 mg/ 100 g. be given as a . bolus of 2.5 g, between one-third and one-half Magnesium . salts may be which usually suppresses of the dose initially required to administered prophylactically in arrhythmias within 20-30 control oedema. patients on diuretics, at doses of seconds, or at a dose of 40 mg/ Unnecessarily high doses of 7.5-15 mmol/ day [ 17] divided min in a saline infusion. The lat diuretics are commonly pre between the two principal meals. ter dose is safer in patients with scribed in the treatment of essen All magnesium salts currently 'respiratory or cardiac insuffi tial hypertension. This practice used prophylactically (chloride, ciency and can be continued should be avoided by applying gluconate, citrate, aspartate) are indefinitely without any detecta simple rules to the choice of a equally well absorbed. All ble rise in the serum Mg level. suitable therapeutic regime. recommended doses apply to a Alternative parenteral dosage Loop diuretics are of little prac standard adult type of 70 kg regimes may be used. tical value in the chronic mono body weight. During prolonged treatment therapeutic treatment of uncom Arrhythmias developing du with diuretics, Mg should be plicated essential hypertension ring treatment with diuretics res taken orally as a prophylactic [73-75, 77, 108] since they do pond to Mg replacement [21, 23]. measure at a dose of 10-15 not satisfy all the criteria where The intravenous administration mmol (20-30 mEq)/day.This by an antihypertensive diuretic of Mg sulphate normalises intra dose should be ·doubled if evi is defined. The minimal effective cellular concentrations of both K dence of Mg depletion appears. antihypertensive dose of antihy . and Mg in skeletal muscle of The Mg formulations available pertensive distal tubular diuretics patients with hypomagnesaemia for therapy (chloride, aspartate) is approximately one-quarter of and hypokalaemia secondary to are equally well absorbed and the standard diuretic dose. Daily prolonged diuresis, whereas sim should be taken in divided doses doses as small as 12.5 mg ple K replacement does not res at meal times. hydrochlorothiazide [9] or chlor tore the intracellular levels of The only absolute contraindi thal~done [26, 57] or 2.5 mg inda either cation to normal [21, 23]. cation to Mg administration is an pamide [76] should be prescribed Despite a relatively poor correla excessive accumulation of the in most cases of uncomplicated tion between the intracellular Mg ion which sometimes occurs in 96 Reyes et al. I Diuretics· and magnesium Magnesium-Bulletin 3/84

patients with acute or chronic secondary hyperaldosteroni~m below 3.5 mmolll. This treat , renal insufficiency with a glome caused by· diuretics is reinforced ment decreases the K concentra rular filtration rate below 30 ml/ and urinary K losses tend to tion gradient between the cell min, hypothyroidism, viral hepa increase [37, 97] (Fig. 7). For this and the milieu interieur. Treat titis, or Addison's disease and in reason, apparently contradictory ment should not be prolonged patients on lithium therapy. experimental and clinical obser after the normalization of kalae Hypermagnesaemia .is diagnosed vations exist with respect to the mia, since it promotes aldoster when the plasma level exceeds effects of restriction of Na intake one secretion (Fig. 7) and may 1.20 mmol/1, but clinical evi on urinary K excretion [37]. In provoke serious side effects, even dence of Mg overload seldom our experience, a daily diet con when slow-release forms are used appears at levels below 2 mmol/1 taining 90-150 mmol of Na is [47]. [92]. Initially, nausea and vomit compatible with minimal ing, rashes, somnolence and 24-hour urinary K excretion in reduction of deep tendon patients without oedema (hyper References reflexes develop. The ECG dis tensives and controlled patients [ l] Akera, T., Brody, T. M.: The role of pays prolongation of the PR with cardiac renal or hepatic Na+, K+-ATPase in the inotropic action of digitalis. Pharmacol. Rev. interval and disturbances of insufficiency) under chronic 29(1978) 187-220. intraventricular conduction. diuretic treatment at standard [::i] Altura, B. M.: Magnesium and When the plasma Mg ·level doses. Whenever possible it is regulation of contractility of vascu reaches 5 mmol/1, skeletal mus desirable to determine the lar smooth muscle. Adv. Microc. 11 cles, including respiratory mus amount of dietary N a that min (1982) 77-113. [3] Altura, B. M., Altura, B. T.: Mg, cles, may become paralysed, with tmtzes urinary K excretion Na, and K interactions and coro cardiac arrest in diastole likely if during chronic diuretic treatment nary heart diseases. Mag. Exp. the plasma Mg concentration in each patient. For this purpose, Clin. Res. 1 (1982) 241-265. rises to 7.5 mmol/1. Accordingly, a trial-and-error procedure [4] Altura, B. M., Turlapaty, P. D. M. V.: Withdrawal of magne plasma levels should be moni should be followed in which sium enhances coronary arterial tored during treatment with Mg standardized diets .with a known spasms produced by active agents. supplements. Therapy should be Na content are given and the Brit. J. Pharmacol. 77 (1982) withdrawn and temporary treat 24-hour urinary K optput eval 649--659. ment with a loop diuretic insti uated. [5] Altura, B. T.: Type-A behavior and coronary vasospasm: a possible tuted if mild hypermagnesaemia role of hypomagnesemia. Med. develops; if important cardiac Hypotheses 6 (1980) 753-757. complications due to Mg excess Administration ofpotassium salts [6] Altura, B. T., Altura, B. M.: The are diagnosed, Ca (as calcium role of magnesium in etiology of The intravenous administra strokes and cerebrovasospasm. gluconate) 100-200 mg should tion of K salts seems to suppress Mag. Exp. Clin. Res. 1 (1982) be infused intravenously over some serious ventricular arrhyth 277-291. 5-10 minutes. mias provoked by diuretics, but [7] Altura, B. T., Altura, B. M.: With this effect is transient, while the drawal of magnesium causes vaso overall myocardial electrolyte spasm while elevated magnesium Low-sodium diet produces relaxation of tone in cere· derangement remains uncor bral arteries. Neurosc. Letters :ZO Avoidance of significant K rected. However, it is advisable (1980) 323-327. losses should be sought during to coadminister KCl with intra [8] Ames, R. P., Hill, P.: Raised serum . diuretic treatment. The usual venous Mg when K in plasma is lipid concentrations during diuretic treatment of hypertension: a study procedures to achieve this goal below 3.5 mmol/1, in order to of predictive indexes. Clin. Sci. are the prescription of a low-Na ensure maximal antiarrhythmic Mol. Med. 55 (1978) 3lls-314s. diet and the administration of effect. Forty mmol of KCI [9] Berglund, G., Andersson, 0.: Low supplementary K or the copre should be infused in saline over doses of hydrochlorothiazide in hypertension. Antihypertensive scription of a K-sparing diuretic. 10 hours; When acidaemia exists, and metabolic effects. Eur. J. Clin. The rate of interchange alkaline K salts such as. bicar Pharmacol. 10 (1975) 177-182. between Na and K in the distal bonate or gluconate should be [10] Bersohn, M. M., Shine, D., Ster· convoluted tubule depends, used [61, 62]. man, W. D.: Effect of increased amongst other factors, on the The chronic oral administra magnesium on recovery from ischemia in rat and rabbit hearts; amount of Na in the preurine at tion of KCl as a prophylactic Anier; J. Physiol. 242 (1982) H89· the interchange level. Restriction procedure has no rational basis H93. of Na intake decreases the fil when the diuretic dose is mini· [ll] Bloch, R, Steimer, C., Welsch, M., tered Na, preurinary Na and mal, N a intake is optimal and Schwartz, J.: L'effet hypocalciu rique de !'hydrochlorothiazide, de consequently, the urinary K out Mg intake is supplemented. Oral la chlorthalidone, de l'indapamide put (Fig. 7). However, if dietary preparations of KCl should only et de l'acide tienilique. Therapie 36 Na restriction is too rigid, the be given when serum K falls (1981) 567-574. Magnesium-Bulletin 3/84 Reye8 et al. I DiuFetics and magnesium 97

[12] Boehringer, K .. Meier, A., Weid· Curr. Ther. Res. 28 (1980) [39] Halidmann, B.: Importance cli mann, P., Schifjl, H., Mordasini, 735-.-740. nique du metabolisme du magne7 R., Riesen, W.: EinfluB von [27] Fischer, B., Fischer, U.: Magnesium sium. Schwei~. Med. Ws.chr. 112 Hydrochlorothiazid/ Amilorid in der Inneren Medizin, Pathophy (1982) 1366-1368. allein oder in Kombination mit siologie und Klinik. Mag.-Bull. 3 [40] Hess, P., Weingart, R.: Free mag Alpha-methyldopa auf die Serumli· (1981) 249-275. nesium in cardiac and skeletal poproteine. Schweiz. Med. Wschr. [28] Fischer, P. W. P., Giroux, A.: Leu muscle measured with ion-selective 111 (1981) 525-.-530. cocyte magnesium concentration as microe1ectrodes. J. Physiol. . (Lon [13] Classen, H. G.: Stress and magne an indicator of myocardial .magne don) 313(1981) 14-15. sium. Artery 9 (1981) 182-189. sium. Nutr; Rep. Int .. 26 (1982) [41] Ising, H.: Interaction of noise [14] Condorelli, L.: L'azione degli ion 105-.-113. induced stres~ and Mg decrease. magnesio sulle turbe de l'essitabil [29] Flink, E. B.: Magnesium defi Artery 9 (1981) 205-211. ita. Sistole 25 (1973) 135-165. ciency, etiology and clinical spec [42] Johansson •. G., Danielson, B. G., [15] Cronin, R. E., Knochel, J. P.: Mag trum. Acta Med. Scand., Suppl. 647 Ljungha/1, S., Wibel/, L.: Evidence nesium deficiency. Adv. Int. Med. (1981) 125-137. for a disturbed magnesium meta 28 (1983) 509-533. [30] Flink, E. B., .Brick, J. E., Shane, bolism in diabetes mellitus. Mag. [16] Chipperfleld, B., Chipperfield J. R.: S. R.: Alterations of longchain free Bull. 3 (1981) 178-180. Differences in metal content of the fatty acids and magnesium concen [43] Joos, C., Kewitz, H., Reinhold heart muscle in death from tration in acute myocardial infarc Kourniati, D.: Effects of diuretics ischemic heart disease. Amer. tion. Arch. Intern. Med. 141 (1981) on plasma lipoproteins in healthy Heart J. 95 (1978) 732-737. 441-443. men. Eur. J. Clin. Pharitiacol. 17 [17] Davis, W. H., Ziady, F.: The effect [31] Furman, B. L.: Impairment of glu (1980) 251-257. of oral magnesium chloride therapy cose tolerance produced by diure [44] Karppanen, H.: Epidemiological on the QTc and QUe intervals of tics and other drugs. Pharmacal. studies on the relationship between the electrocardiogram. S. Mr. Med. Ther.. 12 (1981) 613-649. magnesium intake ·and cardiovas J. 53 (1978) 591-593. [32] Gliick, A., Weidmann, P., Morda cular- diseases. Artery 9 ( 1981) [18] Dyckner, T., Wester, P. 0.: Effects sini, R., Bachmann, C., Riesen, W., 190-199. of magnesium on blood pressure. Peheim, E., Keusch, G., Meier, A... [45] Leary, W. P., Reyes, A. J.: Antihy Brit. Med. J. 286 (1983) Increased serum low-density lipo pertensive and metabolic effects of 1847-1849. protein cholesterol in men treated a combination of hydrochlorothia [19] Dyckner, T., Wester, P. O.;Magne short-term with the diuretic chlor zide and amiloride. S. Mr. Med. J. sium deficiency contributing to thalidone. Metabolism 29 (1980) 60 (1981) 381-384. ventricular tachycardia. Two cases 240-245. [46] Leary, W. P., Reyes, A .. J.: Piretan reports. Acta Med. Scand. 212 [33] Gliick, · Z., Weidmann, P., Morda ide ·in the treatment of hyperten (1981) 89-91. sini, R., Peheim, E., Bachmann, C., sion. Effects on arterial blood pres· [20] Dyckner, T., Wester, P. 0.: Magne Keusch, G., Riesen, W.: EinfluJ3 sure and several blood variables. S. sium deficiency - guidelines for . einer Diuretikatherapie auf die Se· Mr. Med. J. 60 (1981) 925-928. diagnosis and substitution therapy. rumlipoproteine :-- ein uner" [47) Leary, W. P., Reyes, A. J.: Interac Acta Med. Scand., Suppl. 661 wiinschter · Bffekt? Schweiz. Med. ciones medicamentosas de Ios (1982) 37-41. Wschr.109 (1979) 104-108.. diureticos. Sistole 32 (1982) [34] Grimm, R. H., . Leon, A. S., Hun [21] Dyi:kner, T., Wester, P. 0.: Magne~ 93-114. sium in cardiology. Acta Med. ninghake, D. B., Lenz, K., Hannan, [48] Leary, W. P., Reyes, A, J.: The Scand.; Suppl. 661 (1982) 27-31. P., Blackburn, H.:. Effects of thia" magnesiuric effect of a single dose zide diuretics on plasma lipids and [22] Dyckner, T., Wester, P. Rela· of hydrochlorothiazide in healthy 0.: lipoproteins in mildly hypertensive tion between potassium, magne adults. Curr. Ther. Res. 32 (1982) patients. A double-blind controlled sium and cardiac arrhythrnias. Acta 425-431. trial. Ann. Intern. Med. 94 (1981) Med. Scand., Suppl. 647 (1981) [49] Leary, W. P., Reyes, A. J.: Urinary 7-ll. 163-169. volume and solute flows after a [35] Giillner, H. G., Gill, J. R., Bartter, single dose of chlorexolone in neat [23] Dyckner, T., Wester, P. 0.: Ventri F. C.: <;:orrection of hypokalemia thy adults. Curr. Ther; Res. 32 cular extrasystoles and intracellular by magnesium repletion in familial (1982) 417-424. electrolytes before and after potas hypokalemic alkalosis with tubulo sium and magnesium infusions in pathy. Amer. J. Med. 71 (1981) [50] Leary, W. P., Reyes, A. J., Lockett, patients on diuretic treatment. 578--582. C. J., Arbuckle, D. D., van der By/, Amer. Heart J. 97 (1979) 12-18. [36) Giinther, T., Merker, H.-J., K.: Magnesium and deaths [24] Elmgreen, J., Tougaard, L., Leth, Nawroth, H., lsing, H., Lunkenhei ascribed to ischaemic heart disease ' A., Christensen, M. S.: Elevated mer, P. P., SCharsich, M.: Magne in South Africa. S. Mr. ,Med. J. 64 serum parathyroid hormone con sium, calcium and collagen content (1983) 775-77{). centration during treatment with in various parts of the dog. heart [51] Leary, W. P., Reyes, A. J., van der high ceiling diuretics. Eur. J, Clin. under chronic magnesium defi Byl, K.: Effect of a combination of Pharmacal. 18 (1980) 363-364. ciency. Mag.-Bull. 3 (1981) 59-64. hydrochlorothiazide and amiloride [25] Erdos, J. J., Maguire, M. E.: Inde [37] Haalboom, J. R. E.: Kaliumstof on urinary magnesium excretion in pendent desensitization .of beta wisseling bij gebruik van orale healthy adults. Curr. Ther. Res. 35 adrenergic receptor-regulated mag diuretica (chloortalidon). Hart Bull. (1984) 293-300. nesium transport and cyclic AMP 11 (1980) 159-163. [52] Leary, W. P., Reyes, A. J,, van der accumulation. Mol. Pharmacal. 18 [38) Haiat, R., Lel/ouch, A., Lanfranchi, By/, K.: · Urinary magnesium and (1980) 379-383. J., Witchitz, S.: CoAtinuos electro zinc excretions· after· two different [26] Fa/eh, D. K., Schreiner, A. M .. cardiograpqic r~cording (Hotter single doses of amiloride iri healthy Changes in serum lipids during method) during indaparnide treat adults. Curr.. Ther. Res. 34 (1983) treatment of primary hypertension ment: a study of 40 eases. Postgrad. 205-216. with chlorthalidorte alone and in Med.. J .. 57 (Suppl. 2) (1981) [53J Luomma; H.i, Aromaa;, A., Helmi combination with spironolactone. 68-69. nen, S., Murtdmaa, H., .Kiviluoto, 98 Reyes et al. I Diuretics and magnesium Magnesium• Bulletin. 3/84

L.; Punsar, S., Knekt, P.: Risk of [65] Nordrehaug, J. E.: Malignant lipid metabolism. S. Mr. Med. J. 64 myocardial infarction in Finnish arrhythmia~ in relation to serum (1983) 355~356. men in relation to fluoride, magne potassium values in patients with [81] Reyes, A. J., Leary, W. P.: Farma sium and calcium concentration in an acute myocardial infarction. cologia clinica y usos terapeuticos drinking water. Acta Med. Scand. Acta Med. Scand., Suppl. 647 de Ios diureticos. Temas Med. (Sio 213 (1983) 171-176. (1981) 101-107. Paulo) 4(1980) 199-223. [54] Mahaffee, D. D., Cooper, C. W., [66] 0/haberry, J. V., Leary, ·w. P., [82] Reyes, A. J., Leary, W. P.: Magne Ramp, W. K., Ontjes, D. A.: Mag Reyes, A. J.: Magnesium- distri sium deficiency ptovoked by nesium promotes both parathyroid bution and basic metabolism. S. diuretics. S. Mr. Med. J. 63 (1983) hormone secretion and adenosine Mr; Med. J. 63 (1983) 319-320. 410-412. 3'-5'- monophosphate production [67] Olhaberry, J. V., Reyes, A. 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Circulation 64 (1981) mide on calcium and magnesium · magnesium and zinc excretions 722-729. transport in the rat nephron. Am er. after monodosing healthy volun J. Physiol.l41 (1981) F340-F347. teers with · chlorthalidone. Curr. [56] Massry, S. G.: Role of hormonal Ther. Res. 32 (1982) 128-137. and non-hormonal factors in the [70] Quamme, G. A.: Effect of hypercal cemia on renal tubular handling of .[86] Reyes, A. J., Leary, W. P., van der control of renal handling of mag By/, K.: Urinary magnesium output nesium. Mag.-Bull. 3 (1981) calcium and magnesium. Canad. J. Physiol. 60 (1982) 1275-1280. and flow after tnonodosing healthy 277-280. adults with indapatnide. S. Aft. [71] Quamme, [57] Materson, B. J., Oster, J. R., G. A., Dirks, J. H.: Mag Med. J. 64 (1983) 820--822. nesium transport in the Michael, U. F., Bolton, S. M., Bur nephron. [87] Reyes, A. J., Leary, W. P., Venter, Amer. J. Physiol. 239 (1980) ton, Z. C., Stambaugh, J. E., Mar C. 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