Originalia

Potassium and Magnesium-Sparing Diuretics

M. P. Ryan

Summary chez i) des rats non anesthesies avec une gebnis entspricht der unterschiedlichen Be­ charge saline ii) la clearance renale chez les handlung von Kalium und Magnesium im The renal handling of potassium and mag­ animaux anesthesies iii) des patients avec distalen Tubulus und im Sammelrohr. nesium and the effects of diuretics on these insuffisance cardiaque congestive chroni­ Auch bei Triamteren wurden magnesium­ processes are reviewed. Loop-blocking que. Dans des etudes sur I'animal, une rela­ sparende Eigenschaften nachgewiesen. Die diuretics cause major losses of both potas­ tion dose-reponse a ete etablie pour les ac­ Wirkungen von Aldosteron-Antagonisten sium and magnesium. Thiazide diuretics tions de I'amiloride dans la reduction de sind allerdings noch nicht so eingehend cause major losses of potassium while their !'excretion fractionnee du Mg et du K au nachgewiesen. effects on magnesium excretion are less well cours de la diurese induite par le furose­ established. Evidence has accumulated in mide. Les effets de l'amiloride sur !'excre­ recent years that the potassium-sparing tion du Mg sont moindres que ceux sur diuretics also exert magnesium-sparing !'excretion du K qui est compatible avec un Introduction properties. Experiments from our own traitement different de K et de Mg dans le laboratories and from other investigators tubule distal et le canal collecteur. L'triam­ Congestive heart failure is a disease are reviewed. Amiloride has been demons­ terene est I'diuretique peuvent avoir aussi trated to exert magnesium-sparing proper­ proprietes d'epargne du Mg. Lcs effets des which may be associated with dis­ ties in i) conscious saline-loaded rats ii) re­ antagonistes de I' aldosterone sur l'excretion turbances in the four main cations nal clearance studies in rats iii) congestive du Mg sont mains bien etablis que ceux de namely sodium, potassium, calcium heart failure patients. In animal studies, a l'amiloride. and magnesium. The electrolyte dose-response relationship has been estab­ lished for the actions of amiloride in reduc­ disturbances may be due to i) dis­ ing fractional excretion of magnesium and Zusammenfassung ease-related processes such as hy­ potassium during furosemide-induced Die Behandlung von Kalium und Magne­ poperfusion, tissue anoxia, malab­ diuresis. The effects of amiloride on mag­ sium in den Nieren sowie die Wirkung von sorption, alterations in the renin­ nesium excretion are much less than those Diuretika auf diese Prozesse werden unter­ on potassium excretion and this is compat­ angiotensin-aldosterone system sucht. Schleifendiuretika verursachen be­ and atrial natiuretic peptides or ible with the different handling of potassium triichtliche Verluste sowohl von Kalium als and magnesium in the distal tubule and col­ auch von Magnesium. Thiazid·Diuretika may be related to ii) drug treatment lecting duct. Triamterene has also been verursachen ebenfalls groBe Kaliumverlu­ including treatment with diuretics, shown to have magnesium-sparing proper­ ste, die Auswirkungen auf die Ausscheidung inotropic agents and inhibitors of ties. The effects of aldosterone antagonists von Magnesium sind jedoch noch nicht so on magnesium excretion are less well estab­ the renin-angiotensin-aldosterone gut belegt. In den letzten Jahren hat sich system. lished. herausgestellt, daB kaliumsparende Diure­ tika auch magnesiumsparende Eigenschaf­ In this article, I will review the Resume ten aufweisen. In unserem Labor durchge­ effects of diuretics on the renal ftihrte Versuche sowie Versuche anderer handling of potassium and mag­ L'excretion renale du K et Mg, et les effets Wissenschaftler wurden iiberpriift. Es nesium with particular emphasis on de diuretiques sur I'excretion renale du K et konnte nachgewiesen werden, daB Amilorid Mg seront passees en revue. Lcs diun!tiques eine magnesiumsparende Wirkung hatte i) recent findings which indicate that bloquant l'anse provoquent cependent des bei mit Kochsalzlosung behandelten, nicht some potassium-sparing diuretics pertes urinairs majeurs de K et Mg. Lcs betiiubten Ratten, ii) bei Studien zur Nie­ also exert magnesium-sparing diuretiques thiazidiques provoquent cepen­ renclearance bei ratten, und iii) bei Patien­ properties. Diuretics are used clini­ dent des pertes urinairs majeurs de K mais ten mit kongestiver Herzinssuffizienz. In cally for the mobilization of excess les effects des diuretiques thiazidiques sur Tierversuchen wurde eine von der Dosis l'excretion du Mg sont mains bien etablis. abhangige Wechselbeziehung der Wirkung body fluid in states of oedema in­ Un ensemble de donnees dans ces dernieres von Amilorid auf die Reduzierung der teil­ cluding congestive heart failure. In annees indiquent que les diuretiques epar­ weisen Ausscheidung von Kalium und Ma­ addition to the excretion of gnant le K peuvent avoir aussi certaines gnesium bei Furosemid-induzierter Diurese sodium, chloride and water, diure­ proprietes d'epargne du Mg. Les recherches nachgewiesen. Die Wirkungen von Amilo­ de notre propre laboratoire et celles d'autres rid auf die Magnesiumausscheidung sind tics may also alter the renal han­ chercheurs seront passees en revue. L'ami­ doch wesentlich geringer als die Auswirkun­ dling of other electrolytes including loride ont reduit !'excretion urinaire du Mg gen auf die Kaliumausscheidung, dieses Er· potassium and magnesium. One of

210 Mag.-Bull. 8 (1986) Potassium and Magnesium-Spring Diuretics

the most common and potentially the remaining (10%) of the filtered for potassium the existence of sec­ serious side-effects of diuretic potassium is reabsorbed and the retory mechanisms for magnesium therapy is an increased urinary loss reabsorption at this site may be re­ in the distal tubule and collecting of potassium which may lead to lated to chloride reabsorption [25]. duct is not well established. While hypokalemia and possibly reduced The thick ascending limb of the some workers [4, 20, 37, 51, 59] cellular and total body potassium loop of Henle appears to be the have produced evidence for mag­ concentrations [23, 34, 72]. These major site for reabsorption of mag­ nesium secretion under certain ex­ losses of potassium can be espe­ nesium where approximately perimental circumstances, other cially serious in patients being 50-60% of the filtered magnesium workers [ 1, 9, 41] have failed to treated with cardiac glycosides. is reabsorbed [67]. The distal demonstrate magnesium secretion Although loss of potassium caused tubule and collecting duct are be­ at these sites. The processes and by diuretic agents has received ma­ lieved to be the major regulatory sites involved in the renal handling jor attention, the magnesium losses sites for renal modification of of potassium and magnesium are associated with diuretic treatment potassium homeostasis [25]. Potas­ summarized in tab. 1. have not, to date, received the sium secretory processes are in­ The kidneys can vary excretion same attention. Treatment with volved and potassium secretion is rates of magnesium under different modern diuretics can indeed result subject to control by factors such as conditions. During periods of mag­ in enhanced urinary losses of mag­ sodium delivery, flow rate, acid­ nesium deprivation, the kidneys nesium leading to hypomagnesemia base balance, intracellular potas­ play a major role in reducing uri­ and possibly reduced cellular and sium concentrations, hormonal fac­ nary excretion of magnesium to total body concentrations of mag­ tors including aldosterone [25]. The very low levels. This has been de­ nesium [16, 43, 50, 56, 67]. Diure­ role of the distal tubule and collect­ monstrated in experimental mag­ tic-induced magnesium deficiency ing in the renal handling of mag­ nesium deficiency in animals [72] can itself give rise to serious clinical nesium is less well established com­ and also most elegantly by Shils consequences and furthermore pared to the situation for potas­ [62] in a study of magnesium depri­ magnesium deficiency can interact sium. vation in human subjects. How­ with potassium deficiency and con­ The distal tubule normally reab­ ever, the homeostatic role of the tribute to further losses of potas­ sorbs about 5% of filtered mag­ kidney in maintaining magnesium sium including reductions in in­ nesium [67]. However, the reab­ balance can be interfered with by a tracellular potassium [56]. Impor­ sorption of magnesium in the distal number of drugs currently in tant interactions of magnesium and tubule has been shown to be load­ therapeutic use. A number of drugs potassium will be discussed by a dependent. Accordingly, in the interfere with the renal handling of number of other contributors to presence of diuretics acting at sites magnesium and produce renal this meeting. proximal to the distal tubule, mag­ wasting of magnesium. It is highly nesium transport in the distal probable that magnesium defi­ tubule may be highly significant in ciency will become a more frequent Renal Handling of terms of overall renal handling of and serious clinical problem with Potassium and magnesium. Unlike the situation the increasing usage of drugs which Magnesium interfere with the renal handling of Tab. 1: Renal handling of magnesium. A number of the drugs The kidneys play major roles in potassium and magnesium such as aminoglycoside antibiotics both potassium and magnesium [5, 31, 70], the anticancer drug cis­ Processes and homeostasis. Potassium and mag­ Potassium [Magnesium platin [7, 60] and the immunosup­ Sites Involved nesium are filtered at the pressive agent cyclosporin [68) pro­ glomerulus. The fraction of filtered Filtration Yes Yes duce nephrotoxic lesions which are potassium that is excreted is nor­ Reabsorption Yes Yes associated with renal wasting of mally 5-15% [25], whereas the I) proximal tubule 80-90% 25-35% magnesium. The main groups of fraction of the filtered magnesium II) loop of Henle 10% 60% drugs interfering with renal handl­ that is excreted is normally 3-5% ing of magnesium are diuretics. [67]. In the proximal tubule a ma­ III)distal tubule and collecting duct jor proportion (80-90%) of the fil­ 5% tered potassium is reabsorbed [25] Secretion Yes ? · while a much smaller proportion I) distal tubule and (approx. 25%) of filtered mag­ collecting duct 10-15% ? nesium is reabsorbed at this site % Fractional [67]. In the loop of Henle, most of Excretion 10-15% 2-3%

Mag.-Bull. 8 (1986) 211 Potassium and Magnesium-Spring Diuretics

Effects of Diuretics on the 1. Diuretics Acting in the Theoretically, loop-blocking diure­ renal Handling of Potassium Proximal Tubule tics would be expected to cause ma­ and Magnesium jor losses of magnesium as mic­ Carbonic anhydrase inhibitors are ropuncture studies indicate that known to cause loss of potassium. normally 50-60% of the filtered Tab. 2: Factors influencing the effects of Apart from indirect affects, these magnesium is reabsorbed at this diuretics on the renal handling of potassium agents can directly affect potassium side. It has been demonstrated in and magnesium secretion by actions on transport micropuncture experiments that mechanisms in the distal tubule and furosemide inhibited the reabsorp­ L Type of diuretic including collecting duct [25]. The action of tion of magnesium more that that (a) site of action diuretics on magnesium handling in of sodium [48]. In our own studies (b) duration of action this nephron segment has not been in either conscious saline-loaded 2. Dose of diuretic extensively studied. Acetazolamide rats, inactin-anaesthetized rats or has been reported to cause only a congestive heart failure patients, a 3. Duration of diuretic treatment minimal increase in magnesium ex­ very consistent finding is that the 4. Concurrent drug treatment cretion in man [6]. In another loop-blocking diuretic furosemide 5. Underlying disease process study, acetazolamide (500 mg i. v.) causes large urinary losses of mag­ 6. Nutritional intake of potassium has been reported to acutely reduce nesium [15, 17, 55]. Furosemide and magnesium the renal clearance of magnesium when given at a dose of 40 mg/kg to [28]. Agents causing extracellular saline-loaded rats resulted in an in­ fluid volume depletion such as crease of renal magnesium excre­ When considering the effects of mannitol have been shown to en­ tion to 240% of control value over diuretics on the renal handling of hance magnesium absorption from a 6 hour period as shown in table potassium and magnesium a the proximal tubule [74]. Expan­ Ill [16]. Infusion of furosemide number of factors have to be taken 1 1 sion of the extracellular fluid vol­ (1.0 mg kg- h- ) to inactin-anaes­ into account. These factors are ume by saline infusion decreases thetized rats greatly increased the listed in tab. 2 and will be referred tubular reabsorption of magnesium fractional excretion (%FEMg) of to in the following discussion. In [39]. The phenomenon of exagger­ magnesium [18]. Significantly re­ the case of potassium excretion, ated natriuresis after salt loading in duced lymphocyte magnesium and diuretics which act at sites proximal patients with essential and renovas­ potassium was detected in conges­ to the potassium secretory sites cular hypertension was reported to tive heart failure patients being tre­ (late distal tubule and collection be associated with a marked in­ ated with furosemide [55]. While duct) will cause enhanced loss of crease of magnesium excretion other factors associated with con­ urinary potassium by enhancing de­ [28]. This phenomenon could make gestive heart failure such as malab­ livery of sodium and fluid into the a possible contribution to mag­ sorption, poor perfusion of tissues, distal tubule resulting in stimula­ nesium problems in patients with aldosteronism, digitalis treatment tion of potassium secretion. Most hypertension [58]. The effects of may have contributed to the re­ diuretics cause enhanced urinary mineralocorticoids in increasing duced lymphocyte potassium and losses of potassium with the excep­ magnesium excretion has been sug­ magnesium, it is most likely that tion of diuretics developed to re­ gested to be an indirect action treatment with the loop-blocking duce potassium excretion - the mediated by extracellular volume diuretic furosemide was a major potassium-sparing diuretics. Diure­ expansion [40]. contributory factor. Other inves­ tic drugs can also play a major role tigators [61, 71] have reported clini­ in producing magnesium defi­ cal magnesium wasting resulting ciency. However not all diuretics 2. Diuretics Acting in the from loop-blocking diuretics. cause magnesium loss. In recent years, evidence has accumulated Loop of Henle from our own [13-19, 53-57] and Diuretics such as furosemide, 3. Diuretics Acting in the from other laboratories [22, 28, 44] bumetanide, ethacrynic acid which Early Distal Tubule that some potassium-sparing diure­ block reabsorption in the loop of tics may also exert magnesium­ Henle increase the delivery of fluid It is well established that thiazide sparing properties. and sodium into the distal tubule diuretics cause significant potas­ and thereby stimulate potassium sium-wasting [25]. The potassium­ secretion. Diuretics acting in the wasting effects of thiazides are dose loop of Henle also cause major los­ related [73] and also related to the ses of magnesium in the urine. duration of treatment [73]. In treat-

212 Mag.-Bull. 8 (1986) Potassium and Magnesium-Spring Diuretics

ment of hypertension low doses of terone system. In clinical studies 4.1. Experimental Observations thiazides should be used. Avoi­ involving thiazide treatment other Indicating that Potassium-Sparing dance of higher doses (50 mg hyd­ important factors such as high drug Diuretics also exert Magnesium­ rochlorothiazide) should reduce dosage, concurrent drug treatment, Sparing Actions the magnitude and risk of potas­ underlying disease condition and sium deficiency. The effects of dietary intake of magnesium and 4.1.1. Amiloride and Triamterene thiazides on renal handling of mag­ sodium need to be examined for Tab. 3: The effects of triamterene and nesium are less well established possible contributions to mag­ amiloride on electrolyte excretion in con­ compared to their effects on the nesium losses where such mag­ scious saline-loaded rats renal handling of potassium. A nesium losses have been reported Diuretic number of investigations in experi­ to occur. Yo of Control Values mental animals have failed to de­ (dose) monstrate any significant effects on Na K MG 4. Diuretics Acting in magnesium excretion following Triamterene 297 57 62 acute administration of thiazides the Late Distal Tubule and (25 mglkg) [16, 20, 24, 28, 57]. In our own Collecting Duct Amiloride 325 9 42 studies, bendrofluazide did not al­ (2.5 mg/kg) These diuretics inhibit potassium ter magnesium excretion over a 6 Furosemide 533 368 240 hour investigational period in con­ secretion and are usually divided (40 mg/kg) into two types: scious saline-loaded rats [54]. Infu­ Furosemide plus sion of hydrochlorothiazide did not i) agents such as amiloride and Amiloride 110 32 63 alter the fractional excretion of triamterene whose action is in­ (40 and 2.5 mg/kg) dependent of inhibition of al­ magnesium in inactin-anaes­ Results are given as the mean experimental thetized rats. Likewise in acute ex­ dosterone. total urinary output over 6 hours expressed periments in dogs, thiazide ad­ ii) agents such as spironolactone as a % of the appropriate mean control total ministration caused little change in whose action involves competi­ urinary output over 6 hours. Saline-loaded tive antagonism of aldosterone. rats (2.5 m! of0.9% w/v NaCI solution/lOO g magnesium excretion [20, 24]. Fol­ body weight) served as controls for triam­ lowing intravenous administration Amiloride and triamterene are the terene, amiloride and furosemide treated of hydrochlorothiazide (50 mg) to main ones whose actions do not groups. A furosemide-treated (40 mg/kg) human subjects, no significant alt­ depend on antagonsim of aldos­ group served as a control for the furosemide terone. These drugs act on the lum­ plus amiloride group. Adapted from refer­ eration in magnesium clearance ence (16]. was detected [28]. Some long-term inal side and bind to sodium chan­ studies with thiazide diuretics have nels [21, 27, 65]. The drugs result in suggested that these diuretics do inhibition of sodium reabsorption The results shown in tab. 3 are from promote urinary losses of mag­ and a reduction in the transepithe­ our initial experiments in conscious nesium and result in some lowering lial potential difference [21, 27, 65]. saline-loaded rats [16]. These find­ of plasma magnesium [29, 36, 45, Spironolactone, on the other hand, ings demonstrated that, in this ex­ 66, 69]. However, two recent clini­ depends for its action on competi­ perimental model, both triam­ cal studies have failed to detect sig­ tive antagonism with aldosterone terene and amiloride, at doses (25 nificant intracellular (lymphocyte for binding to steroid receptors. and 2.5 mglkg respectively) that or skeletal muscle) magnesium de­ In clinical settings, the diuresis pro­ exhibited marked natriuretic ef­ pletion in either hypertensive pa­ duced by amiloride, triamterene or fects, had potassium and mag­ tients [10] or renal stone formers spironolactone is very modest and nesium-sparing actions. Further­ [33] treated with hydrochloro­ these compounds are mainly used more, the potassium and mag­ thiazide (50 mg daily for 3-10 in association with diuretics (such nesium-sparing properties of years) [10] or bendroflumethazide as loop-blocking compounds and amiloride were also demonstrated (for more than 5 years) [33]. The thiazides) which act at sites proxi­ during diuresis with the loop-block­ role of thiazide diuretics in altering mal to the late distal tubule. The ing and magnesium-wasting diure­ the renal handling of magnesium is potassium-sparing effects of tic furosemide. Recently, it has therefore not well established. It amiloride have been extensively in­ been reported [8] that during a has been suggested that the effects vestigated in patients being treated 4-week study in rats, amiloride was of thiazides may be secondary to a with thiazides [2, 3, 26, 46, 47, 72] effective in ameliorating changes in delayed action [50]. This delayed and with loop-blocking diuretics plasma and tissue potassium and action may be secondary to altera­ [12, 55, 63, 64, 72, 75]. magnesium induced by furosemide. tions in calcium, parathyroid hor­ Following our earlier studies in mone or renin-angiotensin-aldos- conscious saline-loaded rats, we in-

Mag.-Bull. 8 (1986) 213 Potassium and Magnesium-Spring Diuretics r t

Tab. 4: The effects of amiloride (2.0 mg to that in non-magnesium-loaded 1 1 kg- h- ) on glomerular filtration rate animals. It is therefore unlikely (GFR), urine volume and fractional excre­ tion (%FE) of electrolytes that amiloride acts by inhibiting magnesium secretion. It was also Control Amiloride p value clear from these experiments that GFR 0.99±0.11 0.96±0.09 N.S. the transport process for mag­ 1 (m! min- ) nesium being affected by amiloride Urine could be saturated. volume 5.5 ±0.9 9.0 ±1.3 <0.05 A preliminary report on using mic­ 1 (~tl min- ) ropuncture studies to investigate %FENa 0.57±0.13 2.28±0.17 <0.001 effects of amiloride on renal mag­ .... nesium handling has been pub­ %FEK 21.1±1.9 i3.0 ±0.7 ! <0.001 ... lished [35]. These authors investi­ %FEMg 18.9±4.6J 15.9±3.51 <0.01 gated effects of amiloride (2.0 mg 1 1 Results are expressed as mean ± s. e. mean. Fig. I: Dose-response relationships between kg- h- ) in acutely parathyroidec­ Adapted from reference [17] amiloride dose (0.02, 0.08, 0.20 and tomized rats following infusion of 2.00 mg/kg, h) and the change in the frac­ 1.25 mM Mg. Amiloride reduced tional excretion of magnesium (.6. %FEMg). vestigated the effects of amiloride The effects of amiloride were studied during the fractional excretion of mag­ in a renal clearance model in rats furosemide-induced diuresis (1.0 mg/kg/h). nesium. The fractional delivery of [17]. A summary of the results are The statistical significance of the dose-re­ magnesium to the early distal given in tab. 4. Amiloride (2.0 mg sponse relationship was assessed using a tubule was not affected by 1 1 one-way analysis of variance and an F test kg- h- ) increased urinary volume (p<0.01). Data adapted from reference [18] amiloride. However the fractional and fractional excretion of sodium, delivery of magnesium to the late whereas it reduced the fractional distal tubule was reduced by excretion of both potassium and periments indicated to us that amiloride. The authors interpreted magnesium. Amiloride did not af­ amiloride was exerting some fairly their findings as indicating that fect arterial blood pressure, immediate actions at a renal level amiloride increased magnesium glomerular filtration rate, extracel­ which resulted in reduced urinary reabsorption in the latter portion of lular fluid volume, plasma pH, ul­ magnesium excretion. It must be the distal tubule. trafilterable fraction of magnesium, stressed however that the effects of The mechanisms( s) by which and plasma aldosterone [17]. These amiloride on the renal handling of amiloride exerts magnesium-spar- results indicated that the mag­ magnesium (b. -12% FEMg fig. I) nesium-sparing action of amiloride are much less than the effects of was most likely due to a direct renal potassium handling (b. -80% FEK action and not merely secondary to fig. 2). This finding is compatible -·· extra-renal actions. with the different handling of _,. We further investigated the effects potassium and magnesium by the of amiloride on magnesium excre­ kidney. Secretion of potassium tion during furosemide-diuresis in along the late distal tubule and col­ renal clearance studies [18]. In the lecting duct is a major pathway in presence of furosemide, reabsorp­ the renal handling of potassium tion of magnesium in the ascending [25]. Secretion of magnesium is not limb of the loop of Henle is inhi­ a major pathway on the renal hand­ -70 bited and therefore more mag­ ling of magnesium and indeed the nesium is being delivered to the evidence for magnesium secretion -·· -~ distal tubule and collecting duct. is somewhat controversial [1, 4, 9, -·· We established dose-response rela­ 20, 37, 41, 51, 59]. ... tionships for the effects of We investigated the effects of amiloride on fractional excretion of amiloride under conditions Fig. 2: Dose-response relationship between amiloride dose (0.02, 0.08, 0.20 and potassium and magnesium. The re­ (furosemide diuresis and mag­ 2.00 mg/kg, h) and the change in the frac­ sults are shown in figures 1 and 2. nesium loading) designed to stimu­ tional excretion of potassium (.6. %FEK)· The establishment of dose-re­ late magnesium secretion [19]. The effects of amiloride were studied during sponse relationships for the effects Though amiloride also exerted furosemide-induced diuresis (1.0 mg/kg/h). The statistical significance of the dose-re­ of amiloride on fractional excretion magnesium-sparing properties sponse relationships was assessed using a of both potassium and magnesium under these circumstances, the one-way analysis of variance and an F test in these acute renal clearance ex- magnitude of the effect was similar (p

214 Mag.-Bull. 8 (1986) Potassium and Magnesium-Spring Diuretics

ing properties are probably similar 40 cyte potassium and magnesium be­ to those reported for effects on cal­ 390 fore treatment with amiloride. This cium transport [ll]. This latter au­ ':;! 310 probaly indicates siginificant in­ thor has shown that luminally ap­ ')t. 370 tracellular depletion of potassium ~ 360 plied amiloride inhibited sodium :: AMIIorld• and magnesium in these congestive ...... 310 il 120m•/dl! transport and enhanced calcium E 340 heart failure patients being treated transport only in the late segments E with furosemide. In our acute study ..- 330 of the distal convoluted tubules. 320 (6 day period), amiloride (20 mg/ ! The degree of enhancement of cal­ 5' 310 pcO·on.t day) reduced urinary potassium cium reabsorption was highly cor­ "'f.. 300 and magnesium, increased plasma related with the degree of inhibi­ ~ 290 potassium and magnesium and also

tion of sodium reabsorption indi­ 3 4 6 increased lymphocyte potassium cating that the two actions are in­ and magnesium [55]. The effects of terrelated. Amiloride by blocking amiloride (20 mg) on lymphocyte Fig. 3: The effects of acute administration of sodium channels on the luminal amiloride (20 mgld) on lymphocyte potas­ potassium and magnesium are side of the membrane would result sium in congestive heart failure patients be­ shown in fig. 3 and 4 respectively. in a reduction of the transepithelial ing treated with furosemide. Data adatped Therefore, the effect of amiloride potential gradient. Such a reduc­ from reference [55) in reducing urinary magnesium was tion in transepithelial potential gra­ reflected in increased plasma and dient would be expected to favour duced the urinary clearance of intracellular (at least as indexed by reabsorption of divalent cations magnesium [28]. Other workers lymphocytes) magnesium. such as calcium and magnesium. also showed in normal subjects that More long-term studies on the ef­ Amiloride also inhibits secretion of amiloride ( 5 and 10 mg) tended to fects of amiloride on magnesium potassium and hydrogen ions and reduce the urinary excretion of status in congestive heart failure produces a more alkaline urine. Al­ magnesium when administered patients have also been carried out. kalosis has been shown to reduce alone and amiloride (5 mg) In one study [52], plasma mag­ the fractional excretion of mag­ ameliorated the enhanced urinary nesium was followed monthly for 5 nesium in parathyroidectomized excretion of magnesium elicited by months in cardiac failure patients rats [42]. acute hydrochlorothiazide (50 mg) treated with furosemide. Amiloride While most studies have been car­ administration in normal subjects (20 mg) caused a significant in­ ried out with amiloride, other in­ [50]. crease in plasma magnesium which vestigators have reported mag­ We have reported on the mag­ was sustained for the 5-month nesium sparing actions of triam­ nesium-sparing properties of period. Dyckner and Wester [22] terene in experimental animals amiloride in congestive heart fai­ investigated the effects of 6 months [44]. lure patients treated with treatment with amiloride on muscle furosemide [55]. These congestive magnesium in patients with arterial 4.1.2. Aldosterone Antagonists heart failure patients were found to hypertension or congestive heart The actions of aldosterone an­ have significantly reduced lympho- failure being treated with hydroch­ tagonists on renal handling of mag­ lorothiazide (50 mg). Treatment nesium are less well established. In with amiloride resulted in signific­ 45 ant increases in skeletal muscle acute renal clearance studies in 44 rats, we could not demonstrate any i.u magnesium [22]. One study com­ paring effects of hydrochloro­ direct effects of aldosterone or of .;- 42 • thiazide (50 mg) versus hydro­ the aldosterone antagonist ~ 41 I 4 chlorothiazide (50 mg) plus spironolactone on the renal handl­ ! ing of magnesium [16]. .. .. amiloride (5 mg) reported that z amiloride failed to prevent lower­ !.. 3 ~ 3 ing of plasma magnesium in hyper­ 4.2. Clinical Observations Indicat­ lu tensive patients on long term treat­ ing that Potassium-Sparing Diure­ ?; ment [36]. Lowering of plasma tics also exert Magnesium-Sparing 3 6 magnesium was only detected be­ Actions Time (Oe,.a) tween weeks 18-22 in that study Fig. 4: The effects of acute administration of and amiloride in that combination 4.2.1. Amiloride amiloride (20 mgld) on lymphocyte mag­ nesium in congestive heart failure patients also did not fully maintain plasma Studies in normal subjects demons­ being treated with furosemide. Data potassium levels [36]. trated that amiloride (20 mg) re- adapted from reference [55)

Mag.-Bu/1. 8 (1986) 215 Potassium and Magnesium-Spring Diuretics

4.2.2. Triamterene account. Some actions of aldos­ of amiloride as a potassium conserving terone antagonists may be secon­ agent in severe cardiac disease. British Triamterene has a similar mechan­ dary to extra-renal changes includ­ Heart Journal 35 (1973) 456-461. ism of action as amiloride and some [13] Devane, J., Ryan, M. P.: Urinary mag· ing alterations in extracellular fluid clinical studies have also detected nesium excretion during amiloride ad­ volume. ministration in saline-loaded rats. Brit­ magnesium-sparing properties with ish Journal of Pharmacology 67 (1979) this compound. Studies in normal 493P. subjects showed reduced clearance [14] Devane, J., Ryan, M. P.: Reduced re­ of magnesium following triam­ nal clearance of magnesium during terene administration [28]. Dyck­ amiloride administration in rats. Irish References Journal of Medical Science 149 (1980) ner and Wester [22] demonstrated [1] Alfredson, K. S., Walser, M.: Is mag­ 449. in patients with arterial hyperten­ nesium secreted by the rat renal [15] Devane, J., Ryan, M. P.: The effects of sion or congestive heart failure that tubule? Nephron 7 (1970) 241-247. amiloride and triamterene on urinary triamterene (37 .5 mg) given daily [2] Ambrosioni, E., Tartagni, F., Nac­ magnesium excretion in conscious over a 6-month period resulted in carella, F., Magnani, B., Ferreri, C.: saline-loaded rats. British Journal of Comparison of diuretic, natriuretic and Pharmacology 72 (1981) 285-289. increased muscle magnesium com­ K-sparing effects of amiloride and [16] Devane, J., Ryan, M. P.: Diuretics and pared to patients treated for a simi­ triamterene used alone or combined magnesium excretion. Magnesium-Bul­ lar time period without addition of with hydrochlorothiazide. Drugs Ex­ letin 3 (1981) 122-123. triamterene to their therapeutic re­ perimental Clinical Research 6 (1980) [17] Devane, J., Ryan, M. P.: Evidence for 709-722. a magnesium-sparing action by gimen. [3] Antcliff, A. C., Beevers, D. G., Hamil­ amiloride during renal clearance ton, M., Harpur, J. E.: The use of studies in rats. British Journal Phar­ 4.2.3. Aldosterone Antagonists amiloride hydrochloride in the correc­ macology 78 (1983) 891-896. tion of the hypokalaemic alkalosis in­ [18] Devane, J., Ryan, M. P.: Dose-depen­ The findings concerning aldos­ duced by diuretics. Postgraduate Medi­ dent reduction in renal magnesium terone antagonists and magnesium cal Journal 47 (1971) 644. clearance during a frusemide induced conservation are not quite as exten­ [4] Averill, C. M., Heaton, F. W.: The diuresis in rats. British Journal of Phar­ sive or convincing as those reported renal handling of magnesium. Clinical macology 80 (1983) 421-428. for amiloride. In experimental Science 31 (1%6) 353-360. [19] Devane, J., Ryan, M. P.: Reduction by [5] Bar, R. S., Wilson, H. E., Mazzaferri, amiloride of renal magnesium clear­ studies, using the rat renal clear­ E. L.: Hypomagnesemic hypocal­ ance in magnesium-loaded rats during ance model, we could find no evi­ caemia secondary to renal magnesium frusemide diuresis. British Journal of dence for acute effects of either wasting. Annals Internal Medicine 82 Pharmacology 80 (1983) 481P. aldosterone on the aldosterone an­ (1975) 646-649. [20] Duarte, C. G.: Effect of chlorothiazide [6] Barker, E. S., Elkington, J. R., Clark, and amipramizide (MK 870) on the tagonist potassium canrenoate on J. K.: Studies on the renal excretion of renal excretion of calcium, phosphate renal clearance of magnesium [ 16]. magnesium in man. Journal Clinical In­ and magnesium. Metabolism 17 (1968) In a study on the effects of vestigation 38 (1959) 1733-1745. 420-429. spironolactone (100 mg) in conges­ [7] Bell, D. R., Woods, R. L., Levi, [21] Duarte, C. G., Chomety, F., Giebisch, tive heart failure patients over a J. A.: Cis-diamminedichloroplatinum­ G.: Effect of amiloride, quabain and induced hypomagnesaemia and renal furosemide on distal tubular function in 5-month period no beneficial effect magnesium wasting. European Journal the rat. American Journal of Physiol­ on plasma magnesium was noted Cancer and Clinical Oncology 21 ogy 221 (1971) 632-640. [52]. Under similar conditions, (1985) 287-290. [22] Dyncker, T., Wester, P. 0.: Intracellu­ amiloride produced an increase in [8] Borchgrevink, P. C., Jynge, P.: Mag­ lar magnesium loss after diuretic ad­ nesium und potassium changes follow­ ministration. Drugs 28, Suppl. 1 (1984) plasma magnesium [52]. ing prolonged administration of 161-166. However, some workers have re­ furosemide and amiloride in growing [23) Editorial: Potassium in heart failure. ported that spironolactone exerts rats. Journal American College of Nut­ British Medical Journal I (1977) 469. magnesium-sparing properties [22, rition 4 (1985) 380. [24] Eknoyan, G., Suki, W. N., Martinez­ 32, 38, 43]. Dyckner and Wester [9] Brunnette, M. G., Vigneault, N., Car­ Maldonado, M.: Effects of diuretics on riere, S.: Micropuncture study of mag­ urinary excretion of phosphate, cal­ [22] reported that spironolactone nesium transport along the nephron in cium and magnesium in thyroparathy­ (100 mg) given over a 6-month the young rat. American Journal of roidectomized dogs. Journal of period resulted in increased muscle Physiology 21:1 (1974) 891-896. Laboratory and Clinical Medicine 76 magnesium in patients treated with [10] Cohen, L., Kitzes, R., Schneider, H.: (1970) 257-266. The myth of long-term thiazide-in­ [25] Giebisch, G., Malnic, G., Berliner, R. diuretics. The discrepancy in re­ duced magnesium deficiency. Mag­ W.: Renal transport and control of sults obtained with aldosterone an­ nesium 4 (1985) 176-181. potassium excretion. In: Brenner, B. tagonists may at least be partly ex­ [11] Costanzo, L. S.: Comparison of cal­ M. and Rector, F. 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216 Mag.-Bull. 8 (1986) Potassium and Magnesium-Spring Diuretics

tients. New England Journal of and magnesium during reduction in diac failure. British Journal of Clinical Medicine 275 (1966) 1215. their filtered loads. American Jour­ Pharmacology 18 (1984) 268P. [27] Gross, J. B., Kokko, J. P.: Effects of nal of Physiology 213 (1967) 1218- [53] Ryan, M. P.: Magnesium and potas­ aldosterone and potassium-sparing 1244. sium-sparing effects of amiloride- re­ diuretics on electrical potential differ­ [40] Massry, S. G., Coburn, J. W., Chap­ view and recent findings. Magnesium 3 ences across the distal nephron. Jour­ man, L. W., Kleeman, C. R.: The ef­ (1984) 274-288. nal of Clinical Investigation 59 (1979) fect of long-term deoxycorticosterone [54] Ryan, M. P., Phillips, 0.: Diuretic­ 82-89. acetate administration on the renal ex­ induced calcium and magnesium excre­ [28] Heidland, A., Hennemann, H. M., cretion of calcium and magnesium. tion in the rat. Irish Journal of Medical Rocket, A.: The role of magnesium and Journal of Laboratory and Clinical Science 146 (1977) 303. substances promoting the transport of Medicine 71 (1968) 212-219. [55] Ryan, M. P., Ryan, M. F., Counihan, electrolytes. Acta Cardiology 17, [41] Massry, S. G., Coburn, J. W., Klee­ T. B.: The effects of diuretics on lym­ Suppl. (1973) 52-75. man, C. R.: Renal handling of mag­ phocyte magnesium and potassium. [29] Higgins, B. A., Nassim, J. R., Collins, nesium in the dog. American Journal Acta Medica Scandinavia, Suppl. 647 1., Hilb, A.: The effect of bendro­ of Physiology 216 (1969) 1460-1467. (1981) 153-161. fluazide on urine calcium excretion. [42] Marone, C. C., Sutton, R. A. L.: Ef­ [56] Ryan, M. P., Whang, R.: Interrelation­ Clinical Science 27 (1964) 459-462. fects of acute metabolic acid-base ships between potassium and mag­ [30] Hollifield, J. W., Slaton, Jr., P. E., changes and furosemide on magnesium nesium. In: Whang, R. (Ed.) Potas­ Moore, L. 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Mag.-Bull. 8 (1986) 217 Potassium and Magnesium-Spring Diuretics

[67) Sutton, R. A. L., Dirks, J. H.: Renal Medica Scandinavia, Suppl. 647 (1981) tic diuretic. Gastroenterology 59 (1970) handling of calcium, phosphate and 145-152. 833. magnesium. In: Brenner, B. M. and [72] Whang, R., Welt, L. G.: Observations Rector, F. C.: The Kidney, 551-618. in experimental magnesium depletion. Acknowledgements Saunders. Philadelphia (1981). Journal of Clinical Investigation 42 The author wishes to acknowledge [68] Thompson, C. B., Sullivan, K. M., (1963) 305-313. June, C. H., Thomas, E. D.: Associa­ [73] Whelton, A., Watson, A. J. S.: The the excellent collaboration of Pro­ tion between cyclosporin neurotoxicity incidence of hypokalaemia and hyper­ fessor T. B. Counihan, Drs. and hypomagnesaemia. Lancet ii kalaemia associated with diuretic use. Michael F. Ryan and John Devane (1984) 1116-1120. In: Potassium in Cardiovascular and in the studies of diuretics carried [69] Wacker, W. E. C.: The effect of hyd­ Renal Medicine. Ed. by Whelton, P. rochlorothiazide on magnesium excre­ K., Whelton, A., Walker, W., Gordon. out in his laboratory. tion. Journal of Clinical Investigation Marcel Dekker, New York (1986), The expert secretarial assistance of 40 (1961) 1086-1087. p. 237-254. Mrs. Naomi FitzGerald in the pre­ [70] Watson, A., Coffey, L., Keogh, B., [74] Wong, N. L. M., Quamme, G. A., Sui­ paration of this manuscript is McCann, S. R.: Severe hypomag­ ton, R. A. L., Dirks, J. H.: The effect of greatly appreciated. nesaemia and hypocalcaemia following mannitol on divalent ion transport in the gentamicin therapy. Irish Medical kidney. Journal of Laboratory and Clini­ (Autor: Michael P. Ryan, Department of Journal 76 (1983) 381-383. cal Medicine 94 (1979) 683. Pharmacology, University College Dublin, [71] Wester, P. 0., Dyncker, T.: Diuretic [75] Yamada, S., Reynolds, T. B.: Fosters Avenue, Blackrock, Co. Dublin/Ire­ treatment and magnesium losses. Acta Amiloride (MK 870), a new antikalure- land)

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