Interactions between magnesium and drugs in the treatment of .hypertension

W. P. Leary

Zusammenfassung Summary Resume Der Herzmuskel kann ungi.instig durch The heart may be adversely affected by Les medicaments antihypertenseurs peu­ eine antihypertensive Medikation beein­ antihypertensive medications causing vent avoir un effet prejudiciable sur le fluBt werden, die Magnesium (Mg2+) magnesium (Mg2+) depletion or reduced creur en provoquant une depletion en -Verarmung verursacht oder den Influx inflow of the ion across the sarcolemma. magnesium (Mg++) ou une diminution dieses Ions durch das Sarcolemma redu­ Common diuretics cause hypermagnesi­ de !'influx de !'ion a travers le sarcolem­ ziert. Die iiblichen Diuretika fi.ihren zu uresis as may the angiotensin converting me. Les diuretiques usuels, de meme que Hypermagnesiurie, die auch durch den enzyme (ACE) inhibitor captopril. Some le captopril, un inhibiteur de !'enzyme de Hemmer von ACE (angiotensin conver­ calcium antagonists interfere with Mg2+. conversion de l'angiotensine, provoquent ting enzyme), das Gaptopril, verursacht entry to the myocardium. Single doses of une hypermagnesiurie. Certains inhibi­ werden kann. Einige Calcium-Antagoni­ various diuretics including clopamide teurs calciques interferent dans la pene­ tration de Mg++ dans sten interferieren mit der Mg2+-Aufnah­ 5 mg, chlorthalidone 100 mg, hydrochlo­ le myocarde. Des doses uniques de divers diuretiques - me ins Myocard. Die einmalige Gabe rothiazide 25, 50 mg, xipamide 5, 10, verschiedener Diuretika, eingeschlossen par exemple 5 mg de clopamide, I 00 mg 20 mg, and furosemide 40 mg significant­ de chlortalidone, 25 ou 50 mg d'hydro­ Clopamid 5 mg, Chlorthalidon 100 mg, ly increase 24 hour urinary excretion of Hydrochlorothiazid 25 und 50 mg, Xipa­ chlorothiazide, 5, I 0 ou 20 mg de xipami­ Mg2+. The loop diuretics muzolimine 30, de et 40 mg de furosemide- augmentent mid 5, 10 und 20 mg, und Furosemid 40 mg and torasemide 5, 10 mg and the 40 mg steigert signifikant die Mg2+.Aus­ significativement !'excretion urinaire de postassium-retaining diuretic amiloride 5, Mg+ + sur 24 heures. En revanche, 30 ou scheidung im 24-Stunden-Urin. Die 10 mg do not affect Mg2+ excretion ad­ Schleifendiuretika Muzolimin 30 und 40 mg de muzolimine et 5 ou I 0 mg de to­ versely. Mechanisms whereby common rasemide (diuretiques de l'anse), de meme 40 mg, und Torasemid 5 und l 0 mg sowie diuretics induce MgZ+ excretion are com­ das kaliumretinierende Diuretikum Ami­ que 5 ou 10 mg d'amiloride, un diureti­ plex and may involve" parathyroid hor­ que d'epargne potassique, n'ont pas d'ef­ lorid, 5 und 10 mg, haben keinen negati­ mone and the renin-angiotensin-aldo­ ven Effekt auf die Mg2:t-Ausscheidung. fet prejudicilible sur !'excretion de Mg+ +. sterone system. The beta blocker p,indol­ Les mecanismes Die Mechanismen, iiber die die iiblichen de I'hypermagnesiurie ol, amiloride and the ACE-inhibitor indiuite par les Diuretika die Mg2+-Exkretion induzie­ cap­ diuretiques courants sont topril' all reduce urinary complexes et peuv'ent impliquer la 'parat­ ren, sind komplex und kOnnen Parathor­ losses of Mg2+ which occur in response to acute doses of hormone et le systeme renine-angiotensi­ mon und das Renin-Angiotensin-Aldo­ ne-aldosterone. Le pindolol (beta-blo­ steron-System einschlieBen. Der Beta­ distal tubular diuretics. Some experimen­ tal evidence suggests that Mg2+ deficien­ quant), l'amiloride"et le captopril (un in­ blocker Pindolol, Amilorid und der hibiteur de l'enzyme, de conversion de ACE-Inhibitor Captopril mindern jeweils cy might contribute to the pathogenesis of essential hypertension. Studies in hy­ l'angiotensine) reduisent to us 1es fuites Mg2+-Verluste i.iber den Harn, die nach urinaires de Mg+ + induites par les doses akuter Gabe von Diuretika erfolgen, wel· pertensive patients do not provide con­ vincing support for this postulate. Mg2+ aigutls des diuretiques d'effet tubulaire che am distalen Tubulus angreifen. Eini­ distal. Certaines donnees experimentales ge experimentelle Oaten lassen vermuten, deficiency may he a coronary risk factor. Accordingly MgZ+ depletion should be plaident en faveur d'un role du deficit en daB Mg2+-Mangel an der Pathogenese Mg+ + dans la pathogenie de !'hyperten­ der essentiellen Hypertonie beteiligt ist. avoided during prolonged treatment of arterial hypertension. J'he clinical presen­ sion essentielle, mais les etudes menees Studien an Hochdruckpatienten stiitzen chez des malades hypertendus tation of MgZ+ deficiency is non-specific n'etayent diese Annahme aber nicht i.iberzeugend. pas cette hypothese de fayon convaincan­ but the condition Mg2+-Mangel kann einen koronaren Ri­ should be suspected te. Le deficit en Mg+ + peut constituer un sikofaktor beinhalten. Entsprechend soll­ whenever therapy with magnesiuretics facteur de risque coronarien. 11 faut done te eine Verarmung an MgZ+ wahrend der has been prolonged, particularly when prevenir un deficit en Mg+ + pendant le Langzeit-Behandlung der arteriellen Hy­ other factors favouring the development traitement au long cours de !'hyperten­ pertension vermieden werden. Das klini­ of Mg2+ deficiency are present. · sion arterielle. Le tableau clinique du de­ sche Bild des Mg2+-Mangels ist unspezi­ ficit en Mg++ n'est pas specifique, mais fisch; der Verdacht sollte aber immer be­ un tel deficit doit etre suspecte en cas de stehen bei Langzeit-Behandlung mit traitement prolonge par des medicaments MgZ+-ausscheidenden Diuretika und ins­ magnesiuretiques, surtout s'il existe en besondere dann, wenn andere Faktoren meme temps d'autres facteurs suscepti­ vorhanden ,sind, die die Entwicklung ei­ University of Natal, Durban/South Af­ bles de favoriser le developpement d'une nes Mg2+-Mangels begiinstigen. rica carence en magnesium.

62 . Mag.~Bull. 9 {1987) Interaetions 'betweell magnesium and drugs in .the treatment of hypertension

The to le of magnesium (Mg2+) van der By!, K.;: unpublished)~ Diuretics in the three main in both the healthy and malfunc­ Some ca.z+ antagonists may also groups are not interchangeable in tioning cardiov·ascular system interfere with Mg~ + entry in the the management of hypertension has recently become the focus of myocardium [22, 23]. [69]. Loop diuretics do not con­ increasing research and interest form to the strict definition of [8, 20, 28, 29, 30, 39, 73, 79, 85, antihypertensive diuretics [76] 86, 94, 96, 98]. The magnesium Effects of diuretics on and should not be used as mono­ ion appears necessary for opti­ magnesium turnover therapy for uncomplicated hy­ mal regulation of electrical phen­ pertension; they are useful when omena at the sarcolemma and hypertension and renal insuffi­ also, in certain circumstances, for Diuretics and the treatment of ciency coexist, in treatment of the maintenance of an appro­ hypertension hypertensive crises and when the priately low tone in the coronary The diuretics most commonly coadministration of Na +-retain­ arterial musculature. Magnesium used at present are divisible into ing antihypertensives such as va­ deficiency may be complicated three groups in accordance with sodilators and some sympathetic by clinically important cardiac their principal sites of action blockers has caused a syndrome arrhythmias and has also been within the kidney. Loop diuretics of pseudo-resistant hypertension identified as an important risk such as furosemide, muzolimine, [76]. Early distal tubular diuret­ factor for cardiac ischaemic epi­ piretanide and bumetanide exer­ ics are widely employed as drugs sodes including myocardial in­ cise their main renal effect at a of ftrst-choice for the monother­ farction [3, 20, 28, 94]. Most of common site located in the thick apy of uncomplicated essential the adverse cardiovascular ef­ ascending segment'1of the loop of hypertension and their use in fects associated with Mg2+ defi­ Henle. Early distal tubular di­ combination with other antihy­ ciency may be accounted for by uretics, including the thiazides, pertensive substances is also ac­ the induction of significant intra­ chlorthalidone, clopamide, inda­ cepted practice in many coun­ cellular electrolyte imbalances pamide and xipamide, act at spe­ tries [50, I 00]. The K +-retaining including increases in cytosolic cific acceptors for each substance diuretics are not used as monoth­ Ca2+ and Na+ and a decrease in erapy but in the first portion of the distal are sometimes admin­ cytosolic K + [3, 39, 64, 95]. istered with convoluted tubule. The K +-re­ antihypertensive di­ The heart may be adversely af­ uretics in order to limit the taining diuretics spironolactone, sever­ fected by antihypertensive for­ ity of electrolyte imbalances as­ amiloride and triamterene act mulations which promote Mg2+ in sociated with the prolonged use the terminal depletion or reduce the inflow of part of the distal of these substances. the ion across the sarcolemma convoluted tubule where they in­ and the antihypertensive efficacy hibit transparietal exchange be­ Diuretics of these substances could also be tween Na +, which is normally and magnesium deple­ unfavourably affected by der­ reabsorbed from the pre-urine, tion anged Mg2+ turnover within vas­ and K+ and H+ which are ex­ Potassium deftciency secondary cular tissues. Common antihy­ creted fromthe milieu interieur. to increased urinary losses of the pertensive diuretics are known to In view of their widespread clini• ion has usually been identifted as augment urinary Mg2+ excretion cal use, loop and tubular diuret­ the most important cause of car­ and may thus alter the balance of ics can be referred to together as diac arrhythmias developing du­ the element adversely, particu­ common diuretics [65]. The stan­ ring prolonged therapy With larly if other potential causes of dard diuretic dose of a loop di­ common diuretics [27, 31, 32, 57, Mg2+ deficiency are present [6, uretic is that which causes a simi­ 59]. In fact there is no clear rela­ 40, 60, 65, 66, 68, 71, 72, 74, 75, lar natriuretic response to furo­ tionship between plasma K con­ 90, 96, 97]. semide 40 mg assuming the drugs centration and the incidence of Captopril increases urinary are given as single doses to heal­ cardiac arrhythmias during pro­ Mg2+ output acutely in healthy thy individuals under carefully longed treatment with diuretics; individuals given single doses controlled circumstances [65, when appropriate laboratory stu­ (100 mg) of the preparation 76]. Under similar experimental dies were carried out Mg2+ de­ whereas the newer angiotensin conditions the standard dose of pletion appeared of greater relev­ converting-enzyme inhibitors en­ an early distal tubular diuretic ance and supplementation of this alapril and perindopril do not would have comparable effects element suppressed the arrhyth­ share this characteristic ([45, 48] to hydrochlorothiazide 50 mg mia irrespective of the plasma Reyes, A. J., Leary, W. P. and [65, 76]. K+ concentration [10, 15, 52, 56,

Mag.-Bull. 9 (1987) 63 58, 61, 87, 95, 99]. These findings Tab.~ 1: Percentage changes}Ij ir)ean 24-h urinary outputs of fluid and various electro­ justify careful evaluation of the lytes, after administration uf' single doses of various diuretic formulations to healthy role common diuretics play intp­ volunteers, with reS:pect to corr~spondirig mean control 24-h outputs tal Mg2+ turnover. % Diuretic % o/o o/o o/o The effects of single doses of urine Formulationn Cl- Na+ K+ Mg2+ various diuretic formulations volume upon 24-hour urinary outputs of fluid and electrolytes have been 13 Amiloride 5 mg 19* 10 39** -28*** -5 13 Amiloride l 0 mg 43**** 32**"' 65**** 32*** -7 studied in healthy biologically 9 Clopamide 5 mg 25**** 83*** 85**** 25* 27*** equivalent volunteers [67]. Un­ 9 Chlorthalidone der the strictly controlled condi­ lOOmg 69*** ISO**** 165**"'* 70*"'* 87*"'* tions applied, all the diuretics 13 Hydrochlorothiazide used with the exception of tora­ 25mg 21**"'* 29**** 33**** 21 73**** semide 5 mg induced significant 19 Hydrochlorothiazide increases in 24-hour urinary out­ 50mg 38**** 64**** 61 **** 30* 25* 13 Xipamide 5 mg 20**** 39**** 41*** 41 *** . 28*** puts of Cl in comparison with 13 Xipamide 10 mg 63**** 107"'*** 120"'*** 55"'** 50**** placebo and, with the exception 13 Xipamide 20 mg 63**** 102**** Ill**** 80**** 40**** of muzolimine and torasemide 9 Furosemide 40 mg 50*** 49** 48*** 51* also increased 24-hour Na + ex­ 10 Muzolimine 30 mg 14*** 38**** 33"'** 21 9 cretion (Tab. 1). Torasemide, 10 Muzolimine 40 mg 10 24** 18* 32* 11 which has a significant diuretic 14 Torasemide 5 mg -4 23 28 -2 ll effect during the first 6 hours 14 Torasemide lOmg -6 44* 26 1 2 after dosing did not ,increas,e 24 hour fluid output. Urinary K + n = number of cases Significances of the differences between mean control post-dosing 24-h urinary out- output was significantly reduced puts: · by amiloride 5 and I 0 mg and * p < 0.05 was unaffected by low doses of ** p < 0.02 hydrochlorothiazide (25 mg) or **"' p < 0.01 muzolimine (30 m g); standard **"'* p < 0.001 doses of all common diuretics tested significantly increased 24- also increase urinary Mg2+ ex­ monotherapy of hypertension hour urinary K + excretion. Ami­ cretion acutely in healthy sub­ with different diuretic fomulla­ loride had no statistically signifi­ jects. Amiloride does not affect tions significantly reduced cant effect upon 24-hour Mg2+ Mg2+ excretion [26, 42]. Thus; plasma Mg2+ concentration but output although a weak tendency on the basis of actue experiments only after at least 12 weeks treat­ to retain Mg2 + in a dose-depend­ in healthy individuals, it appears ment [37, 38, 44] (Figs. l and 2). ent manner was detectable. The that common diuretics that cause loop diuretics muzolimine (30, clinically significant natriuresis 40 mg) and torasemide (5, I 0 mg) induce hypermagnesiuresis Mecbanisms of diuretic induced had no significant effect on 24- which might be expected to lead hypermagnesiuresis hour urinary Mg2 + excretion to Mg2+ depletion in some indi­ Urinary Mg2+ output in man viduals subjected to prolonged whereas the other common di­ normally ranges from uretic formulations, including fu­ treatment with these prepara­ tions. No data are available on 4 to 8 mmol.day-1 (100-200 mg.day-1). rosemide 40 mg, hydrochloroth­ The manner in which Mg2+ is iazide 25 and 50 mg, chlorthali­ the effects in hypertensives of done 100 mg, clopamide 5 mg chronic treatment with diuretics handled by different areas of the and xipamide 5, 10 and 20 mg all upon total body or myocardial nephron is unknown in man and, increased Mg2+ output signifi­ Mg2+ content. However several for lack of suitable evidence, is cantly with respect to placebo. studies have shown _that a· fall in usually assumed to resemble that Data from other sources confirm plasma Mg2 + concentration ·oc­ in the rat despite the obvious that furosemide 40 mg causes hy­ curs in many patients treated limitations of such an approach.­ permagnesiuresis under similar with common diuretics for pro­ In rats 20-30 % of filtered Mg2 + experimental conditions [26] and longed periods [15, 18, 99]. Pros­ is reabsorbed at the proximal prove that the loop diuretic pire­ pective studies, carried out in an convoluted tubule, 50-60 % at tanide [84] and the early distal area where the diet is frequently the thick ascending portion of tubular diuretic tienilic acid (5] deficient in Mg2+, showed that the loop of Henle, and 1-5 % at

64 Mag,-Bull. 9(1987) ... plretanide 12 mg.d-:-1 hydrC)chlorothl'a.zlde 100 mg crease in PTH would tend to -4 n:9 and amlhulcie. 10 mg.• c;r~1 augment Mg2+ reabsorption at · n :14 . 0e the nephron [54]. When Mg2+ ..§ intake is high and no other cause 0,85 of Mg2+ deficiency is present, .! 0,85 f f loop diuretks . are unlikely to ~ 0,80 0,80 cause significant depletion of the 01 ion since intestinal Mg2+ absorp- 1111 e t t tion tends to increase when ---P<0,02 e 0,75 0,75 plasma concentrations fall [67]. ::1 .. P<0,01 l At present no information is : 0,70 . 0,70 available concerning the effects upon serum Mg2+ concentra­ 0 4 8 12 9 4 8 12 tions of chronic therapy with weeks weeks the· loop diuretics muzolimine Fig. I: Changes in ser~m Mg2+ concentration (mean ± S.E.M.) during the treatment and torasemide. Muzolimine of patients suffering from essential hypertension with piretanide 6. mg b.i.d. or with a (30,40 mg) and torasemide combination of hydrochlorothiazide 50 mg and amiloride 5 mg b.i.d. n = number of cases. Adapted from [37] Leary and Reyes, l981b (left hand panel) and [38] Leary and (5,10 mg) ([47] Reyes, A.J., Reyes. l98la (right hand panel), by courtesy of South African Medical Journal Leary, W.P and van der Byl, K.: unpublished did not increase hydrochlorothiazide 50 mg.d-1 hydrochlorothiazide 50 mg 24-hour urinary Mg2+ output sig• n:9 ,and amllorlde 5 mg.d-1 · nificantly in healthy volunteers ..... n:12 (Tab. 1)). This was largely due to ... marked reductions in urinary 4 Mg2+ flows that followed signifi­ ~ 0,85 0,85 cant increases in excretion of the E + element immediately after dos­ E 0,80 0,80 t ing. Thus these preparations, ':1 + 'iii t t· t which are of relatively limited ~ 0,75 tb 0,75 c use in the treatment of hyperten­ (11 \ CO sion, stimulate the mechanisms E t 0,70 0,70 ---1)<0,01 responsible for loop-diuretic-in­ e duced increases in urinary Mg2+ ::1 t .. P<0,05 41 excretion and have the potential Ill 0,65 0,65 to cause Mg2+ depletion in some 0 6 10 14 18 22 0 6 10 14 18 22 patients. (Early distal convoluted weeks weeks tubular diuretics). These com­ pounds, which are drugs of first Fig. 2: Changes in serum Mg2 + concentration (mean ± S.E.M.) during the random choice as monotherapy for un­ and double blind treatment of patients suffering from essential hypertension with hy­ complicated essential hyperten­ drochlorothiazide 50 mg or with a combination of hydrochlorothazide 50 mg and ami­ sion, appear to increase renal loride 5 mg. n=number of cases. Adapted from [44] Leary et al., l984b, cou~;tesy of Magnesium-Bulletin Mg2+ excretion in a dose-de- pendent manner (Tab. 1). It is not clear how distal tubular the distal convoluted tubule [63]. of Henle; this appears to be in- diuretics increase urinary Mg2+ Parathyroid hormone (PTH) en­ dependent of the effects loop di- ~xcretion to a significant degree hances reabsorption of the ele­ uretics exert upon Cl- and Na + given that only 1-5% of filtered ment at the loop of Henle .and at the same site. Loop diuretics Mg2+ is reabsorbed in. the distal possibly also at the. distal convo­ increase urinary Ca2+ excretion convoluted tubule, at least in tl:;te luted tubule [54]. thus diminishing plasma Ca2+ rat [63]. The fact that amiloride and increasing PTH levels [21, tends to retain Mg2+ [54, 83] Loop diuretics 24, 54, 55]. The resultant mobilis- suggests the . possibility that ation of Ca2+ and. Mg2+ from Mg2+ might be partially subject Loop diuretics block transparie· bone increases the glomerular fil- to processes similar to those af­ tal reabsorption of Mg2+ at the tration and ultimate excretion of c-~ fecting K + in the terminal por­ thick ascending limb of the loop these cations although the in- tion of the distal convoluted tub-

Mag.-Bull. 9 (1987) 65 Interactions between magnesium,:antl1diu,pqin'tbectreatment of,hypertension

ule [12, 13, 14]. This postulate question urinary excretions of consistent with the hypothesis has been tested in a number of fluid and electrolytes were mea­ that aldosterone is involved in carefully monitored experiments sured in healthy individuals who the control of urinary Mg2+ out­ carried out upon healthy volun­ were given single doses of pla­ put. Since beta-adrenergic block­ teers. cebo, captopril 100 mg, hydroch­ ade might be expected to blunt The effects on urinary electrolyte lorothiazide 25 mg, and a,formu­ renin-mediated increases in al­ outputs of single doses of hy­ lation of captoptil lOO mg and dosterone secretion caused by di­ drochlorothiazide 50 mg, placebo hydrochlorothiazide 25 mg in uretics, studies were carried out and a formulation containing hy­ random order (Fig. 4). Captopril to determine whether beta adre­ drochlorothiazide 50 mg and increased urinary Mg2+ excre­ nergic blockade would decrease amiloride 5 mg were compared tion but reduced hydrochloroth­ diuretic-induced hypermagnesi­ [43]. Whereas both active drugs iazide-induced hypermagnesi­ uresis. A combination of sotalol had significant diuretic and na­ uresis markedly and increased 320 mg and hydrochlorothiazide triuretic actions only hydrochlo­ natriuresis when the two drugs 50 mg was found to increase uri­ rothiazide increased 24-hour were given together. These re­ nary Mg2+ output acutely to the Mg2+ output (Fig. 3). This sug­ sults indicate that captopril is a same extent as a single dose of gested the possibility that di­ magnesiuretic per se [48] and hydrochlorothiazide 50 mg [46]. uretic-induced secondary hyper­ that it probaly counteracts thia­ This result suggested that beta­ aldosteronism might promote ur­ zide-induced Mg2+ losses to adrenergic blockade does not in-. inary Mg2+ excretion [19, 42, some extent by reducing plasma fluence thiazide-induced changes 43]. To further evaluate this aldosterone levels; this finding is . in urinary Mg2+ output, irrespec­ tive of any fluctuations in n:19 0/o 6. tN 24-h URINARY OUTPUT plasma aldosterone levels which might occur. In a subsequent 0 40 60 80 study single doses of the distal tubular diuretic clopamide 5 mg, versug place o the beta-adrenergic blocker pin­ dolo! I 0 mg and a combination pc0,001 of the two were given to healthy volunteers in random order [80]. pc0,001 Pindolol blocked the magnesi­ uretic and kaliuretic effects of clopamide (Fig. 5). This result pcO,OS I appears to endorse the hypoth­ '----~ P<0,001 'J esis that diuretic-induced Mg2+ NS · excretion is partly mediated • throught aldosterone and also provides support for the practice Mg2+ P<0,05 of treating hypertension with a NS ~~NS regimen including both a beta­ adrenergic blocker and a distal tubular diuretic. 2 NS In the controlled experiments re­ ca + ferred to in Tab. I and Fig. 3, 4, NS ~]Ns and 5 urine was collected at spe­ cific intervals after dosing and mean accumulated excretions of D HYDROCHLOROTHIAZIDE 50 mg (HCTZ) solutes as continuous functions • HCTZ U. AMILORIDE 5 mg of time were fitted by a mathe­ matical model (Fig. 6). The Fig. 3: Summary of the results from a study in which healthy volunteers were given time-derivative of this model separate single doses of hydrochlorothiazide 50 mg and of a combination of hydroch­ lorothiazide 50 mg and amiloride 5 mg, double blind and in random order. Bars depict gives the mean urinary flow of percentage changes in mean 24-hr urinary electrolyte output after these diuretic formu­ any solute as a function of time lations with respect to mean post-placebo 24-h renal excretions. n = number of cases; NS non-significant. Adapted from [43] Leary et al., l984a, by courtesy of Current and allows accurate description i Therapeutic Research of the time courses of substances

66 Mag.-Bull. 9 (1987) Interactions between magnesium and drugs in the treatment ofhypertension

excreted in the urine, [70]. This decreases urinary Ca2+ excretion ther drug, was given alone [48]. technique has .provid~d further with resultant hypercalcaemia These findings suggest that cap­ insight into possible mech;misms and a reduction in PTH [1, 11]. topril increases urinary Mg2+ whereby distal tubular diuretics output by a direct action on the induce hypermagnesiuresis. kidney and conversely, under When placebo is given to healthy certain circumstances, may retain Hypermagnesiuresis induced by volunteers the mean urinary Mg2+ by decreasing plasma al­ captopril flows of Na+ and Mg2+ are dosterone levels. almost superimposable [77] A small but statistically signifi­ The overall importance of angio­ (Fig. 7). After the administration cant increase in 24-hour urinary tensin-converting-enzyme (ACE) of a distal tubular diuretic to the Mg2+ output was found when inhibitors in Mg2+ homeostasis same subjects the mean urinary single doses of captopril I 00 mg remains uncertain at present. excretions of Na + and Mg2+ be­ were given to healthy volunteers Acute studies have failed to dem­ come . separated in time; mean [46]. The acute administration of onstrate any acute hypermagne­ Na + flow antecedes Mg2+ flow a combination of . captopril siuretic effect in response to sin­ by several hours (Fig. 8). This I 00 mg and hydrochlorothiazide gle doses of enalapril [45] or per­ finding indicates that some rela­ 25 mg to the same subjects in­ indopril [Reyes, A.J., Leary, tively slow, indirect, mechanism duced a marked increase in 24- W.P. and van der Byl, K.: unpub­ contributes to hypermagnesi­ hour Mg2+ excretion although lished] and no data is available uresis caused by distal ·tubular the increment was significantly from controlled prospective stud­ diuretics. Changes in plasma al­ less than that induced by hy­ ies in which plasma or tissue dosterone levels might account drochlorothiazide 25 mg and Mg2+ levels have been moni­ for this time-lapse, since, when a greater than that which occurred tored during prolonged therapy diuretic is given, plasma aldos­ after captopril lOO mg when ei- with ACE-inhibitors, common terone may peak at approxi­ mately the same time as maximal n:13 0/o b. IN 24-h URINARY OUTPUT natriuresis. Early distal tubular 0 25 so 75 diuretics decrease urinary Ca2+ versus output [1, 2, 11] thus raising placebo plasma Ca2+ and lowering pcO 001 plasma PTH [88]. These changes cause hypermagnesiutesis by de­ NS creasing Mg2+ reabsorption in pc0,001 the loop of Henle and could partly explain the delay in uri­ NS nmmmm J p <'0,05 nary Mg2+ flow with respect to K+ NS 0 NS urinary Na+ flow since the in­ -]P<0,05 crease in plasma Ca2+ and fall in P<0,05 PTH would occur later than maximal natriuresis. P<0,001 mmmtiliilillij-lfMtmmmfD ] p < 0,001 Mg2+ P<0,01 pc0,005 c::::J Pc0,05 Potassium-retaining diuretics pc0,001

When a single dose of a combi­ NS nation of amiloride 5 mg and hy­ ca2• NS. I;;;;-] pc0,05 drochlorothiazide 50 mg was ad­ ~~~~~• NS ministered acutely to healthy in­ NS dividuals no significant change in urinary Mg2+ output occurred I!IHYDROCHLOROTHIAZIDE 25 mg (Fig. 3). However the chronic ad­ OcAPTOPRtL 100 mg • = l!ill u D ministration of this combination Fig. 4: Summary of the results from a study in which healthy volunteers were given may result in increased urinary single doses of hydrochlorothiazide 25 mg, of captopril lOO mg and of a combination Mg2+ losses and hypomagnesae­ of hydrochlorothiazide 25 mg and captoprill 00 mg, double blind and in random order. mia in some hypertensives (Fig. 1 Bars depict percentage changes in mean 24-h urinary electrolyte outputs after the active formulation with respect to mean post-placebo 24-h renal excretion. n num­ and 2), possibly because amilor­ ber of cases: NS - non significant. Adapted from [48] Leary et al., 1985, by courtesy ide, like distal tubular diuretics, of Raven Press/ Journal of Cardiovasvular Pharmacology

Mag.-Bull. 9 (1987) 67 diuretics· or their combination. Tab. 2: Conditions that· may cause J)4g2+ Meanwhile it would be prudent d~.fi!;iencyper s~ oraggravat~ Mg2+ def'i· Ill. Conditions in which various factors ciency ind)l~ed by medication (:luring the coexist whleh negatively affect magne­ to .exercise care in the manage­ treatment of arterial hypertension sium balance ment of hypertensives ·treated (a) Stress with ACE-inhibitors, especially I. Decreased magnesium supply (b) Alcoholism in patients at risk of developing (a) Inadequate intake of Mg2+ (c) Hungry bone syndrome Mg2+ deficiency as a result of (i) Low Mg2+ content in drinking (d) Endocrine syndromes water or dietary constituents (i) Hyperparathyroidism any of the factors listed in Tab. 2. (ii) Parenteral nutrition with low (ii) Hyperthyroidism Mg2+ content (iii) Diabetes mellitus (b) Reduced Mg2+ absorption (iv) Hyperaldosteronism (i) Excessive intake of roughage, (v) Excess of glucocorticoids Calcium-antagonists and magne­ saturated fat or foodstuffs with (e) Protein malnutrition sium high content of oxalate or phy­ (f) Phosphate deficiency tate (g) Metabolic acidosis Calcium antagonists such as ver­ (ii) Malabsorption syndromes in­ (h) Hypercalcaemia apamil, nifedipine and diltiazem cluding (i) Acute pancreatitis .:.... selective malabsorption of (j) Third-term pregnancy are widely used in the treatment Mg2+ (k) Exchange transfusion of hypertension and do not ap­ - gluten enteropathy pear to interfere with the influx - pancreatic insufficiency However more recent studies of Mg+ into myocardial cells with steatorrhoea - tropical sprue and have failed to confirm the find­ [22, 23]. However experimental - radiation damage of the ings in spontaneously hyperten­ evidence exists that some related gastrointestinal tract sive rats [25] and no correlation compounds, including prenylam­ (iii) Short intestine syndromes in· between arterial blood pressure ine, terodiline, fendiline and per­ cluding and 24-hour urinary Mg2+ out­ hexiline, may block the passage - extensive resection of small bowel put. was found. in an extensive of both Ca2+ and Mg2 + across - gastrojejunocolic fistulae epidemological study carried out the sarcolemma. The clinical re­ - jejunoileal bypass in man [36]. Two investigations levance of this observation is ob­ (iv) Biliary fistulae carried out in large groups of hy­ scure at present but the possibili­ (v) Whipple's disease (vi) Intestinallymphectasia pertensives failed to show any ty of causing intracellular Mg2+ derangement in plasma Mg2+ deficiency should be born in 11. Magnesium losses level [64, 93] although a recent mind when these compounds are (a) Enteric study .· in black hypertensives administered together with di~ (i) Vomiting (ii) · Diarrhoea found a weak inverse correlation uretics or when any factor that (iii) Repetitive gastirc aspiration between blood pressure and may promote Mg2+ depletion (iv) Laxative abuse plasma or red cell Mg2+ levels coecists. (b) Excessive sweating (H. Seftel, personal communica­ (c) Renal causes tion). (i) Renal inusfficiency with hyper­ magnesiuresis Attempts have been made to de­ Magnesium deficiency and byper• (ii) Excessive intake of caffeine­ termine whether the urinary containing beverages tension Mg2+ losses induced by common (iii) High Na + intake diuretics compromise their antih­ (iv) Drug-induced hypermagnesi­ Some experimental evidence ex­ IJresis due to diuretics, cispla­ ypertensive effect to any extent. ists to suggest that Mg2+ defi­ tin, amphotericin B, carbenicil­ In one study it was found that ciency could be a factor of im­ lin, gentamicin, tricarcillin, car­ significant mean drops in supine portance in the pathogenesis of diac glycosides, osmoticdiuret­ blood pressure occurred in pa­ essential hypertension. De­ ics (v) ~;:tpansion of extracellular tients chronically treated with creased Mg2+ levels in blood fluid volume common diuretics when supple­ and tissues potentiate vasocon­ (vi) Renal tubular acidosis mentary Mg2+ (15 mmol.day-1) striction caused by humoral (vii) Diuretic phase of acute tubular was added to the therapeutic re­ substances such as catecholam­ necrosis ( viii) Postobstructi ve polyuria gimen [18]. This study was not ines and angiotensin II [3, 4, 33, (ix) Hydronephrosis prospective however and placebo 92] and Mg2+ deficiency· acceler­ (x) Essential familial hypermagne­ for Mg2+ was not administered ates the onset of hypertension in siuresis to the control group. Subsequent spontaneously hypertensive rats (xi) Essential sporadic hypermag­ nesiuresis prospective studies failed to de­ [7] and induces an elevation in (xii) Postrenal transplantation monstrate that dietary supple­ blood pressure of Wistar rats [4]. (d) Excessive lactation mentation with Mg2+ had any

68 Mag.-Bull. 9 (1987) Interactions between magnesium and "drugs. in the treatment o.f hypertension

significant effect upon arterial chaemic heart disease correlates viewed extensively [67] and in­ blood pressure whe.rt adminis­ inversely, with the concentration cludes the presentation of many tered either alone or irt eombina~ of Mg2+ in drinking water [34, non-specific signs and symptoms tion with a diuretic [9, 78]. It 35, 41, 51]. Plasma Mg2+ con­ including anorexia, apathy, mus­ therefore appears unlikely that centration is significantly lower cular weakness and fatigue. Mg2+ deficiency should be con­ in patients with coronary artery Chvostek's and Trousseau's signs sidered of major importance in disease diagnosed by arteriogra­ may be present and cardiac ar­ the aetiology, pathogenesis or phy than in patients with healthy rhythmias, notably atrial fibrilla­ management of most cases of ar­ arteries [53]. Evidence has also tion, ventricular and supraventri­ terial hypertension although it been presented that Mg2+ defi­ cular extrasystoles can be the may be of relevance in indivi­ ciency predisposes to significant presenting featur~ of Mg2+ defi­ dual patients and could contri­ cardiac arrhythmias [67]. ciency. Peripheral tremor involv­ bute to morbidity and mortality These findings add emphasis to ing muscles of the face, tongue from cardiac arrhythmias and in­ the importance of avoiding and limb, ataxia, nystagmus, te­ farction. Mg2+ depletion during the pro­ tany and convulsions may occur. longed treatment of arterial hy­ The existence of Mg2+ deficien­ pertension, particularly since cy should be suspected and Magnesium deficiency and raised blood pressure is a car­ sought whenever therapy with a cardiovascular risk factors diovascular risk factor per se. magnesiuretic has been pro­ Magnesium deficiancy has been longed beyond 4 months and incriminated as a coronary risk particularly if dosage has been Diagnosis of magnesium defi­ factor [3, 28]. Epidemiological ciency studies in Finland and South M­ 280 rica have indicated that the in­ The clinical presentation of -0e cidence of deaths ascribed to is- Mg2+ deficiency has been re- E , .... . Mh) n:9 0/o 6 IN 24-h URINARY OUTPUT ! ...... 140 r:0,9999 . . I'IIZ 0 25 50 75 100 :; ,. pc0,00001 versus E .. <.1:::J "c placebo <..~':: " :::J 0 P<0,001 : : ----, pc0,001 NS NS 24 pc0,001 'i- .t: pc0,001 ... 1 0 16 dM.(dt)- z" E ,. E P<0,05 lttflMMjB J pc0,001 ...... 8 I c il: NS ._1 _...~I p:0,001 ·-" 0 NS ..:::J -... 0 NS • 0 3 6 9 12 24 pc0,01 f hou~ ) pc0,01 clopamlde 5 mg Mg2+ NS n:9 NS INS NS Fig. 6: Top: Mean accumulated urinary Na+ output (dots) after administration of a single dose of clopamide 5 mg per os to NS nine healthy volunteers at time 0 (0800h). 2 Bottom: Mean urinary Na+ flow after ad­ ca "' NS -JNS~~NS ministration of a single dose of clopam­ NS ide 5 mg per os to nine healthy volunteers at time 0 (0800h). The graph has been ev- · aluated as the derivative of the function 11!1 CLOPAMIDE 5 mg in the top panel with respect to time (dM/dt). Any area between the curve and D PINOOLOL 10 mg •=rmmuD the abscissae axis and between any two Fig.5: Summary of the results from a study in which healthy volunteers were given times represents the amount of electrolyte single doses of clopamide 5 mg, of pindolol 10 mg and of a combination of clopamide excreted between the times that consti­ 5 mg and pindolol I 0 mg, double blind and in random order. Bars depict p~rcentage tute the area limits. tm is the time dosing changes in mean 24-h urinary electrolyte outputs after the active formulations with res­ to maximal flow. Adapted from [80] pect to mean post-placebo 24-h renal excretions. n =- number of cases; NS "" non-sig­ Reyes et a!, 1985 by courtesy of Magne­ nificant. Adapted from [80] Reyes et al., 1985 by courtesy of Magnesium-Bulletin sium-Bulletin

Mag.-Bu/1. 9 {1987) 69 '/,' l'- "• high or other factors are present .t:.. 8 tm = 4,4 h which favour the development of 0 Mg2+ deficiencx (Tab. 2). There E is no specific routine biochemi­ E E 4 cal test which estimates total -J ::1 body Mg2+ with any 'accuracy 0 :0 0 but measurement of plasma - 11) 0 -4,) Mg2+ concentration by atomic ->- spectroscopy is of some assist­ -0 ance in the detection of Mg2 + ... 0,2 deficiency which is. usually diag­ -<> 4,) E nosed when total plasma Mg2+ .. ::1 concentration is below 11) 0,1 ...>- 4,) 0.75 mmol.L--1 [17, 81]. However «'' c: c: gl a normal serum Mg2+ level does ... «'' not exclude somatic deficiency ·-::1 E 0 since Mg2+ is mobilis~d from 0 3 6 9 12 24 bone into plasma during the ini­ hours tial stages of somatic depletion. placebo n =13 Prophylaxis and tretment of Fig. 7: Urinary Na+ (top panel) and Mg2+ (bottom panel) flows after the administra­ magnesium deficiency tion of placebo to healthy volunteer subjects at hour 0 af the experiment (0800h). n = number of cases; tm = time to maximal flow after dosing. Adapted from [77] Reyes It should be born in mind that and Leary, 1984d, by courtesy of Brazilian Journal of Medicine and Biological Re­ Mg2+ deficiency develops in re­ search latively few hypertensive patients treated. for prolonged periods with magnesiuretic compounds; ,-., hydroc:hlorothlazlde 25 mg hc:tz nevertheless good clinical prac­ 16 : \ ' (hc:tz) n=13 0,4 tice demands that appropriate .I ' measures be taken to further lim­ it the incidence of this condition. This may be achieved by correct­ ·~0 ing faotorslikelyto induce Mg2+ ...- .#.' deficiency (Tab. 2), selecting for­ ~ : \ -0 30 : .. mulations that limit urinary I \ muz E : \ Mg2+ losses, minimizing diuretic .§ I ' doses, and the administration of 20 I \ ''• I ' / '\ Mg2+ supplements. Magnesium I ', , ' salts should be used prophylacti­ ~ 0,2 • .. cally in patients at risk of devel­ ;;; . . i'o~ • oping Mg2+ deficiency; doses of 0 0 i 0 - <11 Ill 7.5-15 mmol.day--1 should be taken, divided between the main ~ 121 /'',,. amllorlde10mg meals. Dosage may be doubled ·~ ,' ',, (ami) na13 when evidence of frank Mg2+ io·'l:; 0,1 deficiency occurs and can be giv­ lll 6 /~------. if . ~ en in the form of aspartate, 0 0 chloride, citrate, gluconate, lac- p 12 24 hou q1 0 12 24 tate or orotate salts. which are ab­ sorbed to a similar extent [67]. Fig. 8: Urinary Na+ (left hand panel) and Mg2+ (right hand panel) flows after the se­ parate administration of various diuretics (dashed lines) and of corresponding place­ When cardiac arrhythmias devel­ bos (continuos li:nes) to healthy volunteer subjects at hour 0 of the experiments (0800- op during diuretic treatment h). n = number of cases. From top to bottom, adapted from [48] Leary et al., 1985; Mg2+ replacement is indicated; [47] Leary et aL, 1985 and [39] Leary et al., 1983, by courtesy of Raven Press Journal of Cardiovascular Pharmacology, Zeitschrift fiir Kardiologie and Current Therapeutic Re- intravenous magnesium sulphate search, respectively · restores the intracellular concen-

70 Mag.-Bull. 9 (1987) trations of both Mg2+ and K + References ence on urinary magnesium excre­ normal in patients with hypoka­ tion in conscious saline-loaded [I] Ali:m, U:, Costanzo, · L. S. and rats. Br. J. Pharmacol. 72 (1981) laemia and .hypomagnesaemia Chan, J; C. M.: Additive hypocal­ ~85,-289. secondary to prolonged diur~tic ciuric effects of amiloride and hy­ [l3) ~: Dose-dependent reduction in therapy whereas simple K + re­ drochlorothiazide in patients treat­ renal magnesium clearance by ami­ placement has no such effect on ed with calcitriol. Min. Electrol. loride during frusemide-induced Metab. 10 (1984) 379-386. diuresis in rats. Br. J. Pharmacol. either cation [15, 16, 91]. The [2] A/on, U., Wellons, M. D. and Chan, 80 (1983 a) 421-428. possibility of Mg2+ overdosage J. · C; M.: Reversal of citamin-D2- [14] -: Evidence for a magnesiumspar­ is remote, except in individuals induced hypercalciuria by chlo­ ing action by amiloride during ren­ with renal insufficiency. rothiazide. Pediatr. Res. 17 (1983) al clearance studies in rats. Br. J. 117-119. Pharmacol. 'J9 (1983b) 891-896. Further measures which may be [3] Alrura, B. M: and Altura, B. T.: [15] Dyckner, T. and Wester, P. 0.: taken to limit Mg2+ losses in hy­ Magnesium, electrolyte transport Ventricular extrasystoles and intra­ pertensives treated with diuretics and coronary vascular tone. Drugs cellular electrolytes before and aft­ include the coadministration of 28 (1984) 120 142. er potassium and magnesium infu­ K +-retaining Mg2 +-sparing di­ [4] Altura, B. M., Altura, B. T., Gebre­ sions in patients on diuretic treat­ wold, A., /sing, H. and Gunther, T.: ment. Am Heart. J, 97 (197c9) 12- uretics or the coadministration of Magnesium deficiency ·and hyper­ 18. a beta-adrenergic blocking agent. tension: correlation btetween mag­ [16] -: Relation between potassium, The coadministration of a K +-re­ nesium-deficient diets and micro­ magnesium and cardiac arrhyth­ taining and a distal tubular di­ circulatory changes in situ. Science mias. Acta Med. Scand. Suppl. 647 223 (1984) 1315-1317. (1981) 163 169. . . . uretic diminishes the acute mag­ [5] Ambrosioni, E., Tartagni, F., Lusa, [17] -: Magnesium deficiency - nesiuresis caused by the common A., Bassein, L. and Magnani, B.: guidelines for diagnosis and substi­ diuretic but may not fully com­ Effects of tienilic acid used alone tution therapy. Acta Med. Scand. pensate for the· urinary fosses of and in association with triameter­ Suppl. 661 (1982) 37-41. ene or amiloride on urinary excre­ [18) Effect of magnesium on blood K + and Mg2+ which occur du­ tion of electrolytes. Int. J. Clin. pressure. Br. Med. J. 286 (1983) ring prolonged therapy. [40, 44, Pharmacol. Ther. Toxicol. 19 1847-1849. 62, 82, 83, 89]. At present only (1981) 445-449. [19] -: Magnesium defi.ciency in [6] Bellorin-Font, E., Weisinger, J. and congestive heart failure. Acta Phar­ the acute effects of pindolol Pas Martinez, V.: Effects of diuret­ macol. Toxicol. 54 (Suppl. 1) (1984) .upon magnesiuresis are known ics on magnesium metabolism. In: 119-124. and it is uncertain whether pro­ Puschett, J. B. (Ed.): Diuretics. El­ [20] Ebel, H. and Gunther, T.: Role of longed therapy with this or other sevier Science Publishing Co., Inc., magnesium in cardiac disease. J. beta-adrenergic blockers will New York 1984, 174-181. Clin. Chem. Clin. Biochem. 21 [7] Berthelot, A. and Esposito, J.: Ef­ (1983) 249-265. have beneficial effects upon uri­ fe.cts of dietary magnesium on the [21] Elmgreen, T., Tougaard, L., Leth, nary losses of Mg2+ [80]. development of hypertension in the A. and Christensen, M. S.:Elevated spontaneously hypertensive rat. J. serum parathyroid h,ormone con­ Am. Coil. Nutr. 4 (1983) 343-353. centration during treatment with [8] Burch, G. E. and Giles, iD.: The high ceiling diuretics. Eur. J. Clin. importance of magnesium deficien­ Pharmacal. 18 (1980) 363 - 364. cy in cardiovascular disease. Am. [22] Fleckenstein, A.: History of calcium Heart J. 94 (1977) 649-:657. antagonists. Circulat. Res. 52 [9] Cappuccio, F. P., Markandu, N. D .. (Suppl. 1) (1983) 3- 16. Beynon, G. W., Shore, A. C., Samp­ [23] -: Calcium antagonism: History son, B. and McGregor, G. A.: Lack and prospects for a multifaceted of effect of oral magnesium on pharmacodynamic principle. In: high blood pt;essure: a double Opie, L: A. (Ed.): Calcium Anta­ blind study. Br.Med. J. 291 (1985) gonists and Cardiovascular Dis­ 235-238. ease. Raven Press, New York 1984, [10] Caralis, P, V., Materson, B. J. and 9-28. Perez-Stable, E.: Potassium and di­ [24] Fujita, T., Chan, C. M. and Barter, uretic-induced ventricular arrhyth­ F. C.: Effects of oral furosemide mias in ambulatory hypertensive and salt loading on parathyroid patients, ·Min. Electrol. Metab. 10 function in normal subjects. Ne­ (1984) 148-154. phron 38 (1984) 109-114. [11] Costanzo; L.: .Effects. of diuretics [25] Gunther, T., /sing, H;, Babisch, W. on the distal convoluted tubular and Vormann, · J.: Magnesium in­ transport of .calcium. ·In: Puschett, take and blood pressure of sponta­ J. B. (Ed.): Diuretics. Elsevier Sci­ neously hypertensive rats. Mag.­ ence Publishing Co., · Inc., New Bull. 6 (1984) 120-123. York 1984, 169-173. [26] Hamdy, R. C., Vinson, M., Rob­ [12] Devane, J. and Ryan, M. P.: The bins, A. D., Struthers, L. P. L., effects of amiloride and triamter- Chapman, S. F., Norrls, R. J. and

Mag.-BuU. 9 (1987) 71 Interactions between magnesium and drugs in the treatment of hypertension

Shaw, H.L.: 24 hour urinary elec­ [41] Leary, W. P., Reyes,;A. J., Lockett, heart disease. Circulation 64 (1981) trolyte profile following frusemide, C. J., Arbuckle, D. D. and van der 722-729. amiloride and a combination of Byl, K.: Magnesium and deaths as­ [54] Massry, S. G.: Role of hormonal these drugs, Frumil In: Puschett, cribed to ischaemic heart disease in and non-hormonal factors in the J. B. (Ed).: Diuretics, Elsevier Sci­ South Africa, S. Afr. Med. J. 64 control of renal handling of mag­ ence Publishing Co., Inc., New (1983) 775-776. nesium. Mag.-Bull. 3 (1981) 277- York 1984, 363-366. [42] Leary, W. P., Reyes. A. J. and van 280. [27] Holland, 0. B.: Diuretic-induced der. Byl, K.: Urinary magnesium [55] -: Effect of thiazide diuretics on hypokalaemia and ventricular ar­ and zinc excretions after two dif­ calcium metabolism. In: Puschett, rhythmias. Drugs 28 (Suppl. I) ferent single doses of amiloride in J. B. (Ed.): Diuretcis. Elsevier Sci­ (1984) 86-92. healthy adults. Curr. Ther. Res. 34 ence Publishing Co., Inc., New [28] lseri, L. T.: Magnesium in coro­ (1983) 205-216. York 1984, 182...:.184. nary artery disease. Drugs 28 [43] -: Effect of a combination of hy­ [56] Materson, B. J. and Cara/is, P. V.: (Suppl. I) (1984) 151 160. drochlorothiazide and amiloride on Risk of cardiac arrhythmias in rela­ [29] Iseri, L. T. and French, J. H.: Mag­ urinary excretion in healthy adults. tion to potassium. J. Cardiovasc. nesium: Nature's physiologic cal­ Curr. Ther. Res. 35 (1984a) 293- Pharmacol. 6 ( 1984) S493 - 497. 300. cium blocker. Am. Heart. J. 108 (57] Morgan, T. 0., Adam, W. and [44] -: Effects of hydrochlorothiazide (1984) 188-193. Hodgson, M.: Adverse reactions to and amiloride combination on long~term diuretic therapy for hy­ [30] lseri, L. T., Freed, J. and Bures, plasma magnesium in patients with pertension. J. Cardiovasc. Pharma­ A. R.: Magnesium deficiency and essential hypertension. Mag.-Bull. col. 6 (1984) 8269-73. cardiac disorders.· Am. J. Med. 58 6 (1984b) 127- 132. (58] Morgan, T. 0., Carney, S. and (1975) 837-846. [45] -: Effects of enalapril on timed Meyers, J.: Sodium and hyperten­ [31] Johansson, B. W.: Magnesium in­ urinary excretions in healthy ad· sion. A review of the role of so­ fusion in decompensated hypom­ ults: A preliminary study. Curr. dium in pathogenesis and the act­ agnesemic patients. Acta Med. Ther. Res. 35 (2) (1984c) 287-292. ion of diuretic drugs. Pharmacol. Scand. 54 (Suppl. I) (1984) 125- [46] -: Effects of hydrochlorothiazide Ther. 9 (1980) 395-418. 128. plus sotalol on acute urinary elec­ (59] Nordrehaug, J. E.: Malignant ar­ [32] Johansson, B. W. and Dziamski, trolyte excretion in normal sub­ rhythmias in relation to serum po­ R.: Malignant arrhythmias in acute jects. 8. Afr. Med. J. 66 (1984d) tassium values in patients with an myocardial infarction: relationship 680-681. acute myocardial infarction. Acta to serum potassium and effect of [47] -: The effects of single oral doses Med. 8cand. Suppl. 647 (1981) selective and non-selective of muzolimine upon urinary solute 101-107. B-blockade. Drugs 28 (Suppl. I) and fluid excretion. Z. Kardiol. 74 [60] Offerhaus, L.: Diuretic drugs. In: (1984)77- 85. (8uppl. 2) (1985) 135-140. Dukes, M. N. G. (Ed.): Meyler's [33] Kaplan, N. M.: Non-drug treat­ (48] Leary, W. P., R~es, A. J., van der side effects of drugs, 1Oth edition. ment of hypertension. Ann. Intern. By/, K. and Acosta-Barrios, T. N.: Elsevier Science Publishers B. V., Med. 102 (1985) 359-373. Effects of captopril, hydrochloroth­ Amsterdam 1984,370-385. [34] Karppanen, H.: Epidemiological iazide and their combination on [61] Papademetriou, V., Fletcher, R., studies on the relationship between timed urinary excretions of water Khatri, I. M. and Freis, E.: Di· magnesium intake and cardiovas­ and solutes. J. Cardiovasc. Pharma­ uretic-induced hypokalemia in un­ cular diseases. Artery 9 (1981) cal. 7 (1985) 856-62. complicated systemic hyperten­ 190-199. (49] Levine, B. S. and Coburn, J. W.: sion: Effect of plasma potassium [35] -: Ischeamic heart disease: an ep­ Magnesium, the mimic/antagonist correction on cardiac arrhythmias. idemiological perspective with of calcium. N. Eng. J. Med. 310 Am. J. Cardiol. 52 (1983) 1017- special reference to electrolytes. (1984) 1253-1255. 1022. Drugs 28 (8uppl. I) (1984) 17-27. [50] Licht, J. H., Haley, R. J., Pugh, B. [62] Penhall, R. K. and Frewin, D. B.: [36] Kesteloot, H.: Epidemiological stu­ and Lewis, S. B.: Diuretic regimens Plasma potassium levels in hyper­ dies on the relatioilsship between in essential hypertension. Arch. tensive patients receiving fixed­ sodium, potassium, calcium and Intern. Med. 143 (1983) 1694- combination diuretic therapy. Med. magnesium and arterial blood pres­ 1699. J. Aust. I (1980) 376-378. sure. J. Cardiovasc. Pharmacol. 6 (51] Luomma, H., Aromaa, A., Helmi­ (63] Quamine, G. A. and Dirks, J. H.: (1984) 192-196. nen, S., Murtomaa, H., Kiviluoto, Magnesium transport in the ne­ L., Punsar, S. and Knekt, P.: Risk phron. Am J. Physiol. 239 (1980) [37] Leary, W. P. and Reyes, A.: Antih­ of myocardial infarction in Finnish 393-401. ypertensive and metabolic effects men in relation to fluoride, magne­ (64] Resnick, L M., Laragh, J. H., of a combination of hydrochloroth­ sium and calcium concentration in Sealey, J. E. and Alderman, M. H.: iazide and amiloride. S. Afr. Med. drinking water. Acta Med. Scand. Divalent cations in essential hyper­ 60 (198la) 381-384. J. 213 (1983) 171 176. tension. N. Eng. J. Med. 309 (1983) [38] and J.: Pire­ Leary, W. P. Reyes, A. (52] Madias, J. E., Mtidias, N. E. and 888-891. tanide in the treatment of hyperten­ Gavras, H. P.: Nonarrhythmogen­ (65] Reyes, A. J.: Bases farmocologicas sion. Effects on arterial blood'pres­ icity of diuretic-ini:iuced hypoka­ de la terapeutica cardiovascular sure and several blood variables. 8. laemia. Arch. Intern. Med. 144 con diureticos. Arch. Inst. Cardiol. Afr. Med. J. 60 (1981b) 925-928. (1984) 2171-2176. M ex. 51 (1981) 291-303. [39] ~: Magnesium and sudden death. (53] Manthey, J., Stoepp/er, M., Mor­ (66] -: Arritmias cardiacas causadas S. Afr. Med. J. 64 (1983) 697-698. genstern, W., Nusse/, E., Opherk, por deficiencia de magnesio: com­ [40] -: Diuretic-induced magnesium D., Weintraut, A., Wesch, H. and plicacion principal del tratamiento losses. Drugs 28 (8uppl. I) (1984) Kubler, W.: Magnesium and ttace usual con diureticos. Pren. Med. 182-187. metals risk factors for coronary Argent. 70 (1983) 448-456.

72 Mag.-Bull. 9 (1987) Interactions between magnesium· and ,drugs in the treatment of hypertension

[67] -;-: De~eterious effects pf antihy­ . lymphocytes ,.t6 monitor cellular [97] -: Problems with potassium and pertensive treatment on magne­ magnesium and· potassium. Mag.­ magnesium in diuretic-treated · pa­ sium turnover. Progress in Pharma­ Bull. 3 (1981) 113 116. tients. Acta Pharmacol. Toxicol. 54 col. 6 {l) (1985) 51..:.87. [84] Saruta, T. and Rato, E.: The di­ (Suppl. 1) (1984) 59-65. [68] -: Diureticos, deficiencia de mag­ uretic effect of piretanide in man. [98] Whang, R.: Magnesium deficiency: nesio, · meurte subita y enfermedad Arz.-Forsch. (Drug Res.) 30 (1980) causes and clinical implications. coronaria. Rev. Clin. Esp. 174 1807-1812. Drugs 28 (Suppl. 1) (1984) 143- (1984) 205-215. [85] Schipperheyn, J. J.: The pathophy­ 150. [69] Reyes, A. J. and Leary, W. P.: A siology of potassium and magne­ [99] Whang, R., 1]ien, 0. 0., Aikawa, formal method for the therapeutic sium disturbances: a cardiac per­ J. K., Ryan, M. P., Watanabe, A., classification of antihypertensive spective. Drugs 28 (Suppl. l) (1984) Chrysant, S. G. and Fryer, A.: Mag­ diuretics. Curr. Ther. Res. 30 (1981- 120-142. nesium and potassium interrela­ a) 1073-1088. [86] Seelig, M. S.: Magnesium defi­ tionships experimental and clini­ [70] -: A mathematical model for the ciency in the pathogenesis of dis­ caL Acta. Med. Scand. Suppl. 647 clinical pharmacology of diuretics. ease. Plenum Medical Book Com­ (1981) 139-144. Curr. Ther. Res. 30 (l98lb) 227 pany, New York 1980, 141-266. [lOO] Whitworth, J. A. and Kincaid­ 235. [87] Sheehan, J., White, A.: Diuretic-as­ Smith, P.: Diuretics: first line treat­ [71] -: Diuretic therapy, magnesium sociated hypomagnesaemia. Br. ment for hypertension. Int. J. Car­ deficiency and lipid metabolism. S. Med. J. 285 (1982) 1157-1159. diol. 2 (1983) 536- 540. Afr. Med. J. 64 (l983a) 355 356. [88] Singhel/akis, P. N., Nikou, A. E., [72] -: Magnesium deficieny provoked Nicolou, C., Mauromatis, D. and by diuretics. S. Afr. Med. J. 63 Ikkos, D. G.: Effects of thiazide di­ (l983b) 410-412. uretic (bendroflumethiazide) an [73] -: Pathogensis of arrhythmogenic parathyroid function in humans. changes due to magnesium deple­ Acta Endocrinal. Suppl. 261 (1983) tion. S. Afr. Med. J. 64 (l983b) 32-35. 311-312. [89] Svenden, U. G., lbsen, H .. Rasnurs­ [74] -: Cardiovascular toxiCity of di­ sen, S., Leth, A., Nielsen, M. D., uretics related to magnesium deple­ Dige-Petersen, H. and Giese, J.: Ef­ tion. Human Toxicol. 3 (l984a) fects of amiloride on plasma and 351-372. total body potassium, blood pres­ [75] -: Diuretics and magnesium. sure, and the renin-angiotensin-al­ Mag.-Bull. 6 (l984b) 87-99. dosterone system in thiazide­ [76] -: The antihypertensive effeCt of treated hypertensive patients. Clin. diuretics. S. Afr. J. Cont. Med. Pharm. Ther. 34 (1983) 448-453. Educ. 2 (l984c) 85-93. [90] Swa/es, J. D.: Magnesium defi­ [77] -: The magnesiuric effect of sev­ ciency and diuretics. Br. Med. J. eral single doses of xipamide in 285 (1982) 1377- 1378. healthy adults. Braz. J. Med. Bioi. [91] Taylor, S. H.: Diuretics and car­ Res. 17 (l984d) 285-291. diovascular. therapy. Perusing the [78] Reyes, A. J., Leary, W. P., Acosta­ past, practising in the present, pre­ Barrios, T. N. and Davis, W. H.: paring for the future. Z. Kardiol. 74 Magnesium supplementation in (Suppl. 2) (1985) 2-12. hypertension treated with hydro­ [92] Tur/apaty, P. D. M: V., Weinder, R. clorothiazide. Curr. Ther. Res. 36 and Altura, B. M.: Interactions of (1984) 332-340. magnesium and verapamil on tone [79] Reyes, A. J. Leary, W. P. and van and contractility of vascular der Byl, K.: Pathogenesis of cardiac smooth muscle. Eur. J. Pharmacol. arrhythmias induced by diuretics. 74 (1981) 263-272. In: Puschett, J. B. (Ed.): Diuretics. [93] Uza, G., Olimpia, P., Agotha, K., Elsevier Science Publishing Co., Uza, D., Vlaicu, R.: Serum concen­ Inc., New York 1984, 257- 259. · tration of Na, K, Ca, Mg, P, Zn [80] -: Blunting of diuretic-induced and Cu in patients with essential increases in renal magnesium and arterial hypertension. Clin. Exp. potassium outputs by beta-adre­ Hypertens. A6(1984) 1415 1429. nergic blockage in healthy subjects. [94} Wacker, W. E. C.: Magnesium and Mag.-Bull. 4 (1985) 121 M 139. man. Harvard University Press, [81] Rude, R. K. and Singer, F. R.: Cambridge, Mass. and London: Magnesium deficiency and excess. 1980,643-100. Ann. Rev. Med. 32 (1981) 245- [95] Wester, P. 0., Dyckner, T.: Diuretic 259. treatment and magnesium losses. [82] Ryan, M. P., Ryan, M. F. and Cou­ Acta Med. Scand. Suppl. 647 nihan, T. B.: The effects of lym­ (1981) 145 152. phocyte magnesium and potas­ [96] -: The importance of magnesium sium. Acta. Med. Scand. Suppl. ion. Magnesium deficiency - (Author: W.P. Leary M.D., Faculty of 647 (198la) 153-161. symptomatology and occurrence. Medicine, University of Natal, P.O. Box [83] Ryan, M. P., Ryan M. F., Thorton, Acta Med. Scand. Suppl. 661 17039, Congella 4013, Durban/South Af­ L. and Counihan, T. B.: The use of (1982) 3-4. rica)

Mag.-Bull. 9 (1987) 73