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AmericanJournal of Therapeuticsg, 34S-3b7l2OO1l

Bioavailability and Pharmacokineticsof MagnesiumAfter


Adrninistration of Magnesium Saltsto Humans

V.V. Ranadel* and J.C. Somberg2

Therapeutically, magnesium salts represent an important class of compounds


and exhibit 'arious
pharmacologic actioru. Examples of magnesium sults *e ionic magne"irr-
and magnesium citrate
in nephrolithiasis, magrresium salicylate in rheumatoid arthritir, ,i^gn"sium
lyclro"xide as an ant-
acid as well as a cathartic, and magnesium nranclelate as ruinary antislptic.
Variou-s anions abtached
to the cation magnesium, such as oxide, chloride, gluconate, and
lactat e, affect the delivery of the
amounts of elemental magnesium t9 the target siie and_thereby produce
different pha#acc,dy-
namic effects. This review examines the bioaviitaUitity and pharmu*kinuu.s
of various magnesium
L'
salts and correlates pharmacodyrramic action with the structure-activity
relatioruhip.

Keywor.ds:magnesium salts, oral repletion, hypomagnesemia, magnesium


bioavailability, mapFe-
sium depletion, hypermagnesemia.

INTRODUCTION myocardj-al relaxation and improve diastolic dysfturc-


tion. one ca-ndidate to antagonize increased extracel-
Magnesium is known to play a centrar role in cellular lular calcium concentrations is magnesiurn, rvhich
function, and it strongly inJluences the excitability of prevents intracellular calcium accumulation by occu_
the cardiovascular and ner:romuscurar system. Lintil pylng calcium-binding sites. In one recent study,l the
recently, the main reason for the adrninistration of hypothesis that irnprovement in left ventriculir dia-
magnesium has been for the administration in patients stolic function can be brought about by infravenous
with suspected magnesium deficiency. Howeve, now administration of magnesium chtoride was tested..
it is known that-magnesium possessespositive phar_ Magnesium is a powerful vasodilator and. decreases
macodynamic effects, such as in controlling arrhyth- systemic vascular resistance in hyper- and normoten_
and possibly reducing sudden death in myocar_ sive patients with coronary artery disease. This effect
1t1
dial infarction patients. Beneficial effects ure seet r9 atso present in the cotottury irteries and explains
when plasma (extracellular) magnesium concentra_ the significant increase in coronary blood flow after
tions are increased from physiologic to much higher magnesium administration. A reduction in left ven_
pharmacologic concentrations. tricular (LV) end-diastolic pressure is an important
Cardiac dysftrnction in patients with coronary ar- effect of magnesium and might e4plain in part the
tery diseases could be attributed to ischemia-induced action of why intrave:rous magnesium administration
deficient sequestration of calcium into the sarcoplas- in reducing mortality in coronary artery disease com_
matic reticulum. It has been postulated that a subitan- pficated by LV failure. These investigaiorsl also con-
tial decline in intracellular calcium could prohibit dude that, based on their studies, magnesium may be
a clinically valuable drug for reducing the ischernic
1Rush-Presbyter in burden originally from increased LV end-diastolic
n-St, Luke's Medical Center,Chicago z
; Ameri- pressure. Among other magnesium compounds, such
can Instituteof Therapeutics, LnkeBluff,IL.
*Addr ess r cor r as sulfate, oxide, gluconate, md ctrloride are effective
fo espondarce: Rush-presby ter i an-st. Luke's Medi-
ca.lCenter,Departmentof Clinial pharmacology,2242 in promoting continued uterine quiescence in patients
W. Har_
rison Street,Tech 2000, Suite 250, Chicagi IL 50512-3515; recently treated for preterm labor, and magnesium has
e-mail : j somberg@nrsh.edu gained acceptance as a tocolytic dtrg avlrting uter-
ine contractions.
7075-2765@ 2007LippincottWilliamsI Wilkins,Inc.
346
RANADEAND SOMBERG

- Magnesium is primarily an intracenurarcation, and gestive heart failure, tachyarrhythmias, diabetes,


the effect of this is and
4T"g probably owing to its compe_
tition with intracellular
atherosderosis. Magnesium aericiency can result
in
cllcium within ti. *yo*et iul hypocalcemia, hypokalemia, dysp hagia, anemia,
cell. PharmacokineticaUy,the increasein the area cen_
'n- tral nervous system. changes j".f, ai ataxia,
der the curve (AUC) is dependent on the dose vertigo,
of oral and neuromuscurar irritabirig. Th" most corrunon
or parenteral administration. There is not a linear se-
re- .I"ltrolyte abnormalities in chronic congestive
lationship between dose and increasein AUC. ,t"*
Mag- heart failure have been hypomagnesemia, hypokale_
nesium cation-the pharmacologically active
moi_ mia, and hyponatremia. Deficilncies espe.ilffy
ety,-in magnesiumsalts.employed., dr,rg, is report_ _
edly releasedin the small iniestine, the sitE of magnesium and potassium are known to tccur
optimal com_
magnesium absorption. There is also insignificant monly in heart failure as a consequence of reduced
ab- ion
sorption in the colon. Radiolabeledstudie-swith uWt intake or as a resurt of an increased loss in magnesium
indicated that the maximum magnesium absorption owing to diuretic therapy. Magnesium therap! for
de-
occurs within the.ileum.andjejunum, and this process replacement foi ure attainment of p'hut.u.o-
ficigng
occurs at an equar rate throughout the smalr iniestine. logic doses, has been effective in changing hemodialy-
The absorgtiol of magneriorn at physiologic doses sis and in treating arrhythmias. pati-enti with
heart
can be des*ibed aipnasiccurv.. a ut*i portion failure who were treated with angiotensin-converting
indicatespassiveltl diffusion of magnesium"oori a con- enzyme (ACE) inhibitors had significantly
higher in_
centration gradiel!. Magnesium absorption is also tracellular potassium and ma gnesium .o.."r,f,
utions,
minimally affected by die1arycalcium iniake, vitamin yh.l may conhibute to the ,=,r.."r, of ACE therapy.
D, and parathyroid hormor,.. So*e disease In addition, treatment with digoxin and
,t*", ur_ diuretic
sociatedwith malabsorption,such as steatorrheaand agents is influenced by or associated with significant
intestinal bypags surgery may also affect magnesium alteration in magnesium barance. The intrica6 rore
of
absorption. Although serum ievels generally ilay magnesium on a biochemical and. celltrlar level in
not car-
correlate well with clinical efficacy, serum measure- diac cells is crucial in maintaining stable cardiovascu-
ments are still the most widery availabre method Iar hemodynamics and electrophysiology function.
to
assessmagnesium status. Most clinicians, however, Electrocardiographicalry, magnesi,,* duficiency
believe that if long-term tocolysis is achieved.,the causes an increase in heart rate, mildly prolongs
se- the
rum levels are only varid foi avoidance of toxicibl PR and QI{S intervals, significantly profo"g, q,
&
and do not predict efficary. internal, flattens sr-T segments, illd contribites
to the
development of u waves. As a resr.rrtof these findings,
magnesium supplementation mosfly by either
MAGNESIUM AND ISCHEMIC parenteral routes is gaining importance in maintain-
ora-l or
H E A R TD I S E A S E ing health in patients.a
Magnesium absorption primarily takes place in the
Magnesium, a predominantly intracellular cation, is 'istal small intestine with some absorpuor,
in the co-
known to be the fourth -oti abundant cation in the lon. The effectiveness of orar magnesium supplemen-
h*Ln and is second only to potassiumin in- tation is determined by its rate of uptake from
-body the
tracellular metabolism. Magnesium is vital in intestine into blood. If blood magnesium levels
bio- exceed
chemical reactionsand servei as a cofactor for severar a critical renal ttueshold, the e*cess will be rapidly
enzyrnes,many of which involve energy me_ excreted, thereby limiting its availabilify to tissues.
9e]tul-ar
tabolism and protein and nucleic acid synth.rir. Magnesium disappears quickly from plasma after
It i, in-
the.ionized magnesiumthat is physiolofically
active, travenous administration. Transfer of magnesium
11d,.-urrecently as 1999,Wary et al3 de"terminedthe from blood to extravascular space is a fast and
efficient
distribution of magnesium in the ionized form using process/ and the intracellular concentration of magne-
3'P-NMRs
and ion-selectiveerectrodes.other tech- sium is high compared with that in blood. Approxi_
niques are the use of fluorescentindicators and ultra- mately one third of serum magnesium is bound
to
5elJrif-uqation equilibrium dialysis. Approximately albumin. Of the rrrugr,"lrir'r*, approximately
half of the total magnesium in the Uoiy is present {iltergd
25o/oto 30% is reabsorbed proxim ulty, 0;/" to 50%
intracellularly in soft tissue and the othei haliis is
pre- reabsorbed into the ascendTg limb of Henle,s roop,
sent in the bones.Lessthan ro/oof the total magnesium
and ZYo to 5o/" is reabsorbed airt"tty. Biochemi..rly,
content is present in the blood.
magnesium activates ATpase enzymes involved in
Depleted amotrnts of magnesium are implicated in
. establishing and maintaining intracellular electro-
the developmentof severaldiseasestatessuch as con-
lyte balance.
American Journal of Therapeutics(2001) g6)
8 IOAVAILABILI MP HARMAC o KINETICS o F
MAG NESI UIVI
347
The activation of these enzymes resurts in
the hy- addition, experimentarmagnesiumdepretion
drolysis of adenosine triphosphrt (ATp) has been
'a and the re. reported to accelerateatherogenesisin rabbits
sultanttrarumempT* tiaruportof varie of ions. fed a
w high cholesterordiet. Howevir, it shourd be
empha-
9:g,t:qrgnized Mg2*-ATpase is ouabain_sensitive sized that at the present
Mg'* (Na*-K")-ATpise, which is associated time more clinicar stud.iesare
with the gequired to elucidate the clinical rerationshipbetween
transcellular sodium pump. Additionalp the
celtrlar Mg depletion and vascular disease.Magnesium defi-
proton and calcium pumps are believed to
be regu_ ciency and hypomagnesemiaare thougit to
Irt:d. by Mg'*-ATpases.The sodium pump approxi_
regulates mate or contribute to a number of cli'Ical
cellular sodium and potassium concentrations. .or,iitio*,
The
proton
.pump is involved with mitochondrial ATp ldudinq toxicity, congestiveheart failure, hyperten_
gerreration,and the calcium pump preservesintracel_ sion, and cardiac rhythm disturbances.Stidi",
Uy
Iular calcium concentrations.-Ther^" Gottleb et al5 s,rppoit the view that .ecogr,iUon
Vrr;O*- sesare and
treatment of the d-isordersare important i-r tr,"
thought to be foturd in all comparbnents nurn-
and thuy agement of congestiveheart failure, and they
possessother yet unknown functiorrs. found
that acute elevation of serum magnesium
Basedon the observationsof severalinvestigations, concentra-
tion decreases"thefr:q:T., of ,ientricular arrhyth_
currently serum magnesium analysis appear!
to be mias. Teo et al7reported thai intravenous magnesium
clinically the most-practical, acceisible,'and
exped.i_ administration in patients with acute i"r"r.f;or,
tious method of identifipg changes in ,ig-
magnesium nificantly decreasedmortality. The American
homeostases.w-hang et ils Jetermined ser,rm"magne- Heart
sium concentrationsin patients with incidence Associationreconunendsthe use of intravenous
of hy- mag-
pomagnesemia.CgT-gnty found signs and nesium among.the drugs used in the management
symp_ of
toms associatedwith crinical m"gnesl.rm ventricular tachyarrhythmias in patients #in
deficienry acute
and hypomagnesemiainclude sevJralnervous myocardial infarction (AMI). This-recommenda
tion is
system based on the relationship of hypomagneserniato re-
manifestations such as hyT>eractivedeep tendon
re- fractory verrtricular fibrilIauon- ana tJ refractory
flexes that can progress to ataxia, tt"i .'t it po-
g, mentar tassium repletion. In the later phase of AMI,
obtundation, convulsiorrs,and coma. Cer_
emyzynski and van Haos concrlded that treatment
Endocrine causesof magnesium deficiency
incrude with magnesium can be used effectivery to restore
hypgtthyroidism and hyp jraldosteronism,
and excess normal rhythm in patients with ar.hythrnias.
renal lossesof magnesium are associated
with glycos_ Previous reports have suggested that there
uria and . is a
_lppear to be responsiblefor Ure hiftr fre_ sbong correlation between crinical hypokaremia
qY$.I of hypomagnesemii found in d_iabeti.r]CUr,i- and
cally, increased re^ar excretion has been reported ftffomaSnesemia. Whang et ale ,upoited that 42o/o of
in hypokalemic patients weie also hlpo*ugrr.r.*i.
metabolic acidosisassocia ted with starvationl,t"tou"i- or.,
dosis, and alcoholism. The mechanism of this youlne testing of serum magnesiuh coicentrations.
nrpo_ In the same study, hypomalresemia was found
magnesemiaassociatedwith metaboricacidosis in
may 29.%of pider,tJ and,23%of frypophos-
be related to loss of magnesium from bone flpotrutremic
and. phajemlc patients. Therefore,rhis study ,"g[i#
muscle Thus, metaboric acidosis, whether from t],ut
star- in the absenceof routine ser,,'n magnesium
vatiorL ketoacidosis,arcoholicketoacidosis, analysis,
or diabetic the detection of hypokalemi., hypir,atremia,
ketoacidosis,can each contribute to magnesium iypo_
defi- phosphatemia, or hypocarcemiastoua alert the clini-
ciency and hypomagnesemiathrough eicessive
renal cian to order a serum magnesium analysisbecause
magnesium loss.Miscellaneous.",rsls of hypomagne_ of
may rugn probabilif of c6existing nypo*ugo"r"*i".
;emia include excessive lactatior.,,
.*.("lrrt" ir*_ *g
fusions, and acuteintermittelt pgrphyria. ftis is especiallytrue if hypokalemia is obslerved.
C[#cA epi_ There is a close linkagi between magnesium
demiologicsturtiessuggestu,t^i urere,"y u. and
"L,-** potassium concentration not only ctinilaly, as evi_
effect relationshiq b: magnesium aefici"".y "^a dencedby the 42% of hyponatremicpatients'who
vascular lesions.sInT""n- hard-wa-terregions with high are
hlpolagnesemic, but aiso experimentally.
magnesium content, the incidence of atheromatous Magne_
vascular lesions sium-depletedrats have reducel skeletalrriuscre(ieu)
-appears to be decreased.f" pop"f"_ potassiumconcentrationsdespiteprovision
tion studieg, high plasma magnesium concentrations of potas_
sium. This loss is accompaniedby ialiuresis as *"u
nave beenfotrnd in associationwith lower u,
serrunlipid phosphaturia. Lr study, potassium depletion
concentrationsand decreasedcardiovascurar lnother
mortar- was acceleratedwhen m"goesio- deficiency i.,
ity'- Experimental magnesium depletion is "ssociatea ,.r-
perimposed.Restorationol mr.rsclepotassium was im_
hyp er.triglyceridemia, hyp ercholesterolernia,and.
Yi,h peded when coedsting magnesium'depletionwas not
oecreasedhigh-density Iipoprotein concentrations.
Lr concurrently repleted with potassium.'ln vitro studies
American lournal of Therapeutics(200j.) g(S)
348
RANADEAND SOMBERG
using red blood cell membranes have shown that reports of in vivo animal moders of coronary occlusion
magnesium depletion increases membrane permeabil-
and reperfusion" are important conbibutions to the
ity, restrlting in loss of celltrlar potassium and intra-
emergr.ng database the potential benefits of mag-
cellular accumulation of sodi'm. In squid axone and nesium in ischemic 9n heart disease. These reports span
ascites tumor cells, decreased. ATpaie activity has
four different animal species, are complementary, and
be.enreported with magnesium d.epletion. Expostrre to
provide data on magnesium loading it vario's times
a low magnesium concentration causes curtiued car-
along a continuum from a point weil before coronary
diac cells to decrease potassium transport. This effect
occlusion (equivalent primary prevention i. pu-
of low- magnesium concentration occiured primarily
tients) to time points 1o jusi beforl, during, and uite,
on ouabain-sensitive Na*-K*-ATpase. Normally, mag_
coronary occlusion that ranged from 45 minutes to 72
nesium enhances inward rectification of poiassium
hours. The treatment regimerrs are likeiy to have
concentration by blocking cell potassium efflux
yielded blood or tissue concentrations of magnesium
through potassium charurers-.with magnesium depre- "patients
generally consistent with those observed in
tron, pelassium channels become trnblocked because
with AMI who received magnesium in clinicir triars.
of the relative lack of magnesium, resulting in in_
Magnesium infusions can ca'se a multitude of card_io-
creased efflux of cellular poiassium. There is ilso evi-
vascular and local cellular effects. some investigators
dence that potassium and Na-cr cotransport is de-
observed modest reductions in heart rate and aiterial
creased with magnesium depletion. Experimentar ob-
pressure that may have played a protective role but
s er v at ions i n d i c a te th a t th e c a u s e l of cel l ul ar
are unlikely to b. sole explanati-on for the ability of
potassium loss resulting from magnesium depletion F"
magnesium to reduce infarct size. under the experi-
are multifactorial and include kaliuresis, alterld cell
mental conditions of Cfuistensen et u1r",taand Herzog
membrane permeability, decreased Na*-K*-ATpase
t afr3'rs no differences in hemodynamics o, *yo.ur_
activity, decreased inward rectificatioru and decreased
dial blood flow were seen in the magnesium-treated
Na and K cotransport. Thus, it is important to recog_
versus control animals, suggesting that any differ-
nize the pivotal role of magnesium inmaintaining
ce-l- ences observed were lik ly to be du! to a mytcelular
lular potassium homeostaiir. to
effect of magnesium.
Data are accurnulating trmt indicate that magne-
Implications of the experimental data are that mag_
sium cation may be a promising agent for the protec_
nesium deficienry at the time of coronary occlusion is
tion of ischemic myocardium and modulation of
associated with a larger irrfarcf and shori-term admin-
reperfusion injury. Magnesium is a critical cofactor in
ishation of supplemental magnesium jtut before coro-
more than 300 intracellular enzymatic processes, nary artery occlusiory during the time when the coro_
T"^y of which are integrally involved in lt ito"hor,- n1y artgy is occluded, at the time of reperfusiory or
drial ftrnction of energy- production, maintenance of
within 15 to 45 minutes of reperfusion titr,.itr the size
transsarcolemmal ionic gradients, cell volume control,
of the infarct. The benefits of supplemental magne_
and resting membrane potential. The cardiovascular
sium are lost either when there is idelav of more th".
consequences of magnesium deficiency in animal and
15 to 45 rninutes after the onset of reperfusion or when
clinical studies have been summari r"d.ay seeligll and reperfusion is sufficiently late sttch that only negli-
include multifocal necrosis with calcium accumirlation
gible amounts of myocardial tissue are availible ]or
in mitochondria in a pattern reminiscent of myocardi-
salvage. If the coronary artery is subtotally occluded
al ischemia and catecholamine-induced cardiomyopa-
and distal perfusion is maintained, no incremental
thy, atherogenesis, a heightened tendency to piatelet
benefit of magnesium is observed. confirmation of
aggregatron, increased coronary and peripheral vas_
these observations is found in the reports of a greater
cular resistances,sinus tachycardia and refolarization infarct size in magnesirrm-deficient animals anJ of ,e-
abnormalities, and ventricular tachyarrhytn*iu. A re-
duced irrfarct ri?: animals pretreated with magne_
vigw of epidemiologic studies highrightea * inverse T
sium in which AMI is produced by another metiod,
relatioruhip between the magnesium iontent of drink-
ie, isoproterenol infusion.
ing water and ischemic heart diseaserelated mortalify
in various populations.l' Lrtravenous infusions -Although the latest experiments of Cluistensen et
of alrz'rband Herzog et u113'17lend support to the intrigu_
magnesiu* il patients have been reported to red.uce
ing notion that early freatment with magnesium limits
coronary and systemic vascular reiistance, inhibit infalct size by as much as s}o/o,they Jo not conclu-
platelet aggregation, and terminate episodes of tors-
sively establish the mechanism by which magnesium
ade de pointes type ventricular tachyiard.ia.
exerts its benefit. The available data suggerl thut u
Articles published by Christensen et all2 and Her-
combination of mechanisms may act adlitively or
zog et al," when viewed in the context of six other even synergistically to protect myorytes: (1) reduce
American lournal of Therapeutics (2007) S(5)
BIOAVAILABIuMP HARMACOKIN ETICS OF MAG NESIUM
349
vulnerability to oxygen-deprived free radicals, (2) de_ to indicate total bgaymagnesium stores. For the past
crease cytosolic calcium levels by inhibition of inward several decades, the dinical chemistry laboratory has
-sarcolemmal
flux of calcium ions through calcium offered two tests to assessmagnesium status: the total
chan.els and. possible intracellular sites as well, (3) serum magnesium concentration and magnesium ex_
red'ce myocardial oxygen demand via sinus slowing cretion in trrine. These two tests address the output of
and lowering of arterial pressure, (4) coronary vaso_ magnesium but do not provide meaningful infbrma-
dilation and enhancemenl of collateral development, tion about intracellular magnesium. Theie are several
and (5) inhibition-of platelet aggregation and preven- other tests that
tion of coronary tfuombosis. _*uy be of value in assessing magne.
sium status and can-be organized into three groups:
The reduction of infarct size with magnesium has +issue magnesium, physiologic assessment
of magne_
profotrnd research and clinical implications. The Lan- sium, and ionized magnesium.
gendorff model of du Toit and opie18 suggests that to
cardioprotective effects with ma: esium, the Tissue magnesium
,aghieyg
blood level must be elevated before or w:ithin a short
interval after reperfusion of a totally occluded coro- Determinations of total magnesium in tissue, primar-
nary artery by thrombolysis or p"rcrrtaneous translu- ily serum determination, have yielded *ori of the
data
minal coronary angioplasty or after spontaneous -on magnesium. Red blood cells (RBCs) and
reperfusion. Because thrombolysis and spontaneous muscle have also been used to assessmagnesium sta-
reperfusion are both characteriiedby stuttting cycles tus. These tissues predominate in magnlsium deter-
of reperfusion and reocdusion until sustainei reper- minations of tissue content because bt ure ease of
fusion is achieved, magnesium regimens that include blood and muscle specimen collection. Assays for total
a loading bolus and inJusion are probably necessary. tigsue magnesium have two difficulties: ihe physi_
In addition to limitation of myocardial necrosis, such a ologically active component of magnesium (ionized
regimen might also offer protection against stunning magnesium) cannot be specifically determined and in-
and more necrosis should late reocclusion of the in- formation about the total magnesium concentration in
f ar c t - r elat ed a rte ry o c c u r. F i n a l l y , d uri ng the one tissue may not provide information about other
critical early hours of AMI, it is imperative to ma]ntain body pools of magnesium.

T ld:g"ate coronary perfusion pressure: rngnesium_


loaded boluses that are too large, delivered toJrapidly, Serum
or given in conjunction with other vasodilating agents, The optimal specimen for determining magnesiurn is
such as nitrates, may cause a decrease in arterial pres- serurn, rather than plasma, because an additive such
sure lead.ing to a reduction in subendocardial perfusion. as an anticoagulant could be contaminated with mag_
Based on the
-elperimental data or., ,nugoesium in nesium or affect the assay procedure. Because u,r"
AYI, it is possible to formulate hypotheies to help magnesium concentration in RBCs is approximately
understand that yery early administration of magne. three times greater than that in serum, ii is important
sium in an animal infarct model can red.uce infarct size to prevent hemolysis and to harvest the serum
if reperfusion of the artery occurs early. Moreover, promptly. The serrun magnesium concentration is in-
lwo additional animals studies undersiore the fact creased by 0.05 mmol/L with the lysis of RBCs to ef_
that magnesium sulfate decreases myocardial inJarct fect a serum hemoglobin concentration of 41.1 mmol/L.
size when administered before but not after coronary A reference system for magnesium has been estab-
reperfusion. It should be noted that the beneficial ei- [shed by the National Reference system for Clinical
fects of magnesium in the latter two studies were
Laboratories of the National Committee for Clinical
likely the result of a direct myocellular effect as evi- Laboratory standards (NCCLS). The definitive
dencedby the absence of any diffe"ert.e in myocardial method for
blood flow or hemodynamics befween the magne_ {agnesium is isotope dilution/mass spec_
trometry and the reference method is flame atomic
sium-treated and control animals. Furthermore, b| in- absorption specbometry FAAS). standard reference
hibiting catecholamine release, magnesium may pre. material (SRM) 929 is a preparation of magnesium
vent infarct extension.le gluconate dihydrate available from the Natioial Insti-
tute for Standards and Technology (Gaithersbr.ug, MD).
A S S E S S M E NOTF Furthermorg sRM 909 is a human serurn with certi-
M A G N E S I U MS T A T U S fied values for many analytes, including magnesium.
The determination of the total sor'rrr, mJgnesium
Assessing magnesium status is problematic because includes three states: approdmately 600/o is-ionlzed,
there is no simple, rapid, and accurate laboratory test nearly 33% is bound to protein, and the remainin g7o/"

American Journal of Therapeutics(200D 96)


350
RANADEANDSOMBERG
is complexed to phosphate, citrate, and other anions.
f:1"d. no- significant concentrationsin normar
Approximately 7so/oof the protein bound fraction indi-
is viduals. six studies documented no correration
bound to albumin and the remaining zs yo to be-
globu- fween total RBC and total mononucrear brood
lins' The total-serum magnesium concentrations(de- cerl
terlined by FAAS) in the US population were
nor_ ryBq) magnesiumconcentrationsin normal ind.ividu-
als' one study found no correlation between
m-ally distributed with the ceritrur qs percentile totar
for muscle and totar RBC magnesium.However, the
ion-
3lults (aged IB-74) berween 0.25 and O.qS,r*, ot/L. ized RMC magnesium was significantly gieater
Most clinical raboratories rely on a cororimetric in
control subjectswith a normar tdtal sertun m"agnesium
primarily calmagite or merhyl thymol concentrationthan in hypomagnesemicpafidts. fur_
TllY:,usi1g
Drueas the chromophore. The colorimetric proc"d.oes
thermore, when controf indiviiuars were gi; a row
are more susceptible to interference by ei-tdog*ro,rs
and exogenouscompounds compared with faeS. magnesium diet, there was a progressivJ fau in
the
total serum and ionized RBC magnesium concentra-
The total serurn magnesium concentration,imper-
tions' Thus, the ionized RBC magnesium concentra-
fect as it may be, is the entry level test to
evaluate tion deservesfurther sfudv.
magnesium status in humarrs. The serurn magnesium
concentration is. primarily controlred by the"kidney $ranqes in total RBC magnesium have been linked
to the following three diseases:hypertension,premen_
t* dietary of magnesium.Witfr the excep_
::d
tion of bone, theThf.
total serurnmagnesiumconcentration :!1tlt qmdrome (PMS),and chronic fatigue ,1i.,dro-"
(cFS). There is conflicting information for
has not been shown to correl-atewith other total and
tissue ionized RBCmagnesiumin essentialhypertension.
pog! of magneriT. Lr a study of 1. patients, An
Alfrey increase and no change have been rlported for
and Miller2' found a correrationcoefficientof the
0.96be- total RB-qmagnesium concentrationin patients
tween bone and total serum magnesium concentra- with
essentialhypertension compared with iormotensive
tions. other investigators have not confirmed these
controls. For ionize$
results. However,- a portion of the bone magnesium
pertension/one sttrdy\nC lnagnesium in essentialhy-
pool is labile and availabreto partially supiort the fo,nd alignificant d.ecreaseand
another found no significant change compared
serum magnesium concenbation in states of with
chronic normotensivecontrols.Three g.o.tpl fo,nd a decrease
magnesium deficiency. The serurn magnesium
con_ in total RBC magnesium in women with pMS.
centration-maybe of value for relatively icute changes In a
double.blind, randomized study, women with pMS
in the intake or excreti."l magnesium.For "ru*iI",
who received an orar magnesitm preparation (10g0
in a patient treated with ?f furosJmide, a roop dituetic, mg of elementalmagnesium daily) ihowed improved
the concentrationmay decreasesu,Cdenly.'Ho*"rr".,
symptoms over those who received placebo.'l Last,
the relatiolship between the total ,"r..,*'*ugr,esi.rm
patients with CFS had a significant dicrease in total
concentrationand-the total body magnesiumitatus
of RBC magnesium and ben&ted from intramuscurar
a patient is difficurt to interpret ior se"verar
reasons(eg, magnesium. Another study assessed. magnesium sta_
state, distributiory equilibrium). For chronic changes
tus in patients with CFS and in contois using
in magnesium stafus, the serum magnesium the
concen_ magnesiumretention test and found no difference
tration does not provide any signifi&nt information. be-
fween RBC magnesium and the three diseases
Thus, the primary varue of the tid serum *ugnesi.rm previ-
ously described.22 clearry, more researchis neededto
concentration is to determine acute changes
L *ug_ understand the possibrererationship between magne-
nesium status or establisha baselinevaluE.
sium and hypertension, CFS,ana pUS.
Redbloodcells
Mononuclearblood cells
The total RBC magnesium concentrationmay be
de_ The use of the total MBC test as a surrogate for the
termined directly or indirec-tlr usina the total'magne-
estimate of intrac.ellularmagnesiu* *"f proposed
sium concentrationof whorgblood-and the hemato-
during the SecondInternatioial Magnesiuri Sfmpo_
crit. Deuster and colleagues2levaruatedthree meth-
sium in 1976-several studies with nolmal individ.uars
ods (two direct and one indirecg for determining
tot t havenot shown a correlationbetweentotal MBC mag_
magnesium in RBCs and concluded that an in?irect
nesium and that of serum or RBCs.Two stud.iesfound
using nitric acid to lyse the cells was repro-
T.tl".d a correlation betweentotal MBC magnesium and
ducible, reliable, accurate, and easy to p.*orrn. total
Nuclear magnetic resonancespectrosiopy iras lT.l. magnesium in humaru. Dyckner and Westerz
been ini_tiauyfo'nd a correlation (R = .74) between total
used to determine ionized mafnesium in RBCs.The
MBC magnesium and total muscle magnesium con_
total RBCmagnesiumconcentrJtiondoesnot correrate
centrations with nine individuals (tfueJcontrols and
with other tissue poors of magnesium.Three studies
six patientswith hypertension),but the correlationbe-
Anterican lournal of Therapeutics (200L) S(5)
BI OAVAILABILITY/PHARMACOKINETICS OF M AG N ESIIJM
351
came nonsignificant =
_(R .22) when L5 patients with Mg) be administered intravenously as a bolus over 1
congestive heart failure were added tb ttre study.
minute. This is followed by 500 mL ZTo MgSOo (40
sjdgren and colleagues23 fo,nd a significant correla-
tion between total MBc magnesiumlnd total muscle 11ot_Mq) over the next 5 hours. lf necessaryIanother
500 mL 2o/' Mgfr4 may be administered over the next
magnesium in patients with type I diabetes melritus.
10 hours. As with potassium, magnesium therapy is
studies with rats depleted by-administration of furo-
interdicted with onset of renal ]ailure. parenteral
semide did not find a correlation between total MBC
magnesium therapy should be interrupted when-
and total card,iac or skeletal muscle magnesium
con-
centration. Additional studies are needed to deter- 9u9l lypotension (80 mm Hg systolic) ortradycardia
(<50 beats/min) occur, se.om magnesium concentra-
mine the relatio:rship between total MBC magnesium
tioru exceed 2,5 mmol/L or when deep tendon
and total muscle magnesium. Thus, the valu"e re_
of the flexes disappear.
total MBC magnesium test has yet to be determined.
h:r the Iess critically ilf hypomagnesemic patient,
oral magnesium replenishmlnt iJ preferred.. Oral
MuscIe
repletion can be accomprished with mignesium oxid.e,
Muscle is an appropriate and important tissue for the ma gnesium la ctate, and ma gnesi um-con taining anta
c-
assessment of magnesium status because it contai's ids, such as Maalox or Myranta. Gullestad. et"ar25re-
approximately 30% of the total body magnesium. ported that in a group of 40 magnesium_depleted eI-
However, relatively few studies have aetermir.ed total derly patients (average age,7I) rLceiving or.l ,r,ugrr._
muscle magnesium in humans because of the sium (15 mmol daily) repletion was wen torerated.
speciar
gkills and expense of the assay, which involves needle Od.y fotu patienrs (10%)reported mild diarrhea. Mug_
biopsy of the muscle, prepaiation of the tissue, and
lesium repletion was 7 days vs. 5 weeks. This affirms
determination of magnesium by FAAS. severar stud- the importance.of parenteial magnesium repletion in
ies have documented a lack of correlation between treating critically ill patients.
muscle and serum or RBC total magnesium concen- It is estimated that the total body store of magne.
trations' As indicated previously, thi correlation is approximately Zt to 2g g or IT0O to 2300 dpq.
be- :i"T
tween muscle and MBC totar magnesium for humans Maintenance of necessary mfunesium balance re-
is equivocal. More promising iJ the use of nucrear qyT:r a daily dietly intake of it least 24 to 30 mEq,
magnetic resonance spectroscopy to determine ion- which is the official US recommended daily anowance
ized magnesium noninvasively in muscle in vivo. (Pei {1 g Mg = 83.3mEq (41.1mmol) oi1 mMole =
L2 mg =
Yq or 1 mMole )45 *g Mej. The RDA for
men is 350to 400mg, and for wo-er,, the value is 2g0
T H E R A P E U T IIC
M P L I C A T I O NO
SF to 300 mg. For a complete listing of RDAs by gender,
age, and specific condition, the ieader shourd iefer to
M A G N E S I U MR E P L A C E M E N T RDA tables. Accurate measurementof total_body
magnesium level is difficult becauseof the intracellu-
The exact dose re.quirg{ in magnesium deficiency
is lar location of this element. Despite the limitations of
pogrly understood and dosing reconunend.ations vary
the se-^rmmagnesiumlevel, which correspondsto less
widely. It is important to eJtablish the presence
of than 7o/oof total body magnesium, this dltermination
ade.quate renal ftrnction before initiating treatment
is by-far the most availaEreand representsthe most
*ith magnesium. L:r severery ilr hospitatiz"ea patients,
expeditiousmethod of evaluating possible d.isorders
administration of parenter^[ s}o/oMtso, (magrresium
of magnesiummetabolism,A mafnisium ]ever of ress
sulfate) (2.1 mmol Mglml) is the
ireferred irode of than 1.5m
,l.fpy. Flink24 reconunends administering 4g mmol !e/L is consideredhypomagnesernic, and
patientswith magnesiumlevelsgieater th an 2.1Eq/L
of intramuscular magnesium on hospital iay 1 and
are consideredhypermagnesemic.zz
injecting 17 to 25 mmol per day for the next 4 days.
For Data regarding biopharmaceuticsand pharmacoki-
the critically ilf convuriing hypomagnesemic patient,
netics of various magnesium salts appear to be lim-
Flink recommends an intravenous"roading dose
of ited. conscientious effort w.s *"d. to u.quire as
MgSOo
lg tt1 mmol Mg) followed by g mriol for the
remainder of the day. On each of days Z to 5,25 mmol T.,.h data aspossiblefrom the literature (TabIL1) and
the conclusionspresentedhere are basedon the values
Mt is administered in divided dosls, diluted in the
that are reported in this table.
d.ay's intravenous fluids.
The use of magnesiumsulfate (Epsomsalt) as a ca_
In the critically ill magnesium-deficient patient with
thartic in patients with impaired ienal function can
ventricular tachycardia ind / or fibrillation, Iseri et
alzs lead to severetoxicity owing to hypermagnesemia,Al-
recorrunend that 10 to 15 mL 20% Mgso4 (g-12 mmol
though toxicity is uncommon in healthy lubjects, little
American Journal of Therapeuticse00j) g.i.c)
352
RANADEAND SOMBERG
T able 1. M a g n e s i u mc o mp a ri s o nc h a rt.

Magnesium
salts Carbonatea6 Chloride3E* g11r"1"3s,aot Fumaratea3 Gluconate3E* Glycinateas
E lem ent al 2 3 2( 1 s . 0 ) 6 4 (5 .2 6) -(25) 530 (44.16) 27 (2.2,tabl ets) 100 ( 8. 33)
Mg++/
54 (4,4,ti qui d)
dos e,m g
(mEq)
S ofubilit y Nearly High Very good Good Moderate G ood
in water insoluble

B ioav ail- Extremely Go o d Good Good G o o d ;s i m i l a r Good


abilit y low
to chl ori de

O r al abs or p ti o n , 1 9 . 6 8( 1 . 0 4 ) 29.64(ionic) 19.25 ?3. 5


% (mEq) (0.82-0.43)

Delivery Tablets Enteric Li qui d, Tablets Tablets, Ingestion


system coated tablets liquid
tablets
Dosage 70 mg 640 mg/d, 25 mE q Mg, 1 Tablet 648 mg/d, 100mg
e l e me n ta l 1-2 tabs 2-5 tablets 24 tablets
M g (e a c h T ID TID
ta b l e t)
Side effects Gl distress, Gl distress, Laxative, Gl distress,
d i a rrh e a d i a rr hea evacuant di arrhea

Comments Not very Enteric Therapy- Expensive Good


soluble coating limitingside formulationto alternative
at pH of Gl could effects; achieve in pat ient s
tract; some delay limited recommended with
Gl side absorption; absorption; daily intestinal
effects; some low citraturic allowance resection
laxative Gl side response requirements
effects;
cathartic

is known concerning the extent of absorption of mag- The baseline excretion rate of magnesium was signifi-
nesium after a cathartic dose of magnesium sulfatl. cantly conelated with that of creatinine (R = .975j and
The bioavailability of magnesium after a large oral inorganic sulfate (R = .921). AIt the subjects experi-
dose of magnesium sulfate in normal volunte&s *us enced mild or moderate diarrhea. Therefore, the au-
examined in the current investigation. Baseline 2* thors concluded that magnesium is absorbed to a lim-
hour urinary excretion rates of magnesium and creat- ited and variable extent in healthy adults after a ca-
inine were determined over 3 corrsecutive days in six thartic dose of magnesium sulfate.2s
healthy men. The oral administration of 13.d g (56.s Magnesium sulfate is also the agent most commonly
mmole) magnesium sulfate U.S.p., in four equal used for treatrnent of edampsia and prophylaxis in
hourly increments, resulted in the urinary excretion patients with severe pre-edampsia. It is usually glven
(corrected for baseline excretion rate) of 4.0 t 2.9o/o by either the intramuscular or inbavenous route. The
(mean t SD) of the dose of magnesium during the first intramuscular regimen is most commonly a +g intra-
24 hours and 5.0 x, 7.0o/oof the dose during i Z}-hou, venous loading dose, immediately followed by 10 g
interval. Magnesium sulfate administration had no ef- intramuscularly and then by 5 g every 4 hours in al-
fect on the 24-hour urinary excretion rate of creatinine. ternating buttocks. The intravenous regimen is given
e001.) g,5)
AnrericanJonrnalof Therapeutics
BI OAVAILABILITY/PHARMACOKINETICS OF MAG
NESI UM
353

KMg D L L Hydrox-
L-lactateaE,aes Oxide37,4o citrate4l*r aspaft ate4taspartate"t idea+t Salicylats36ll Sulfatea2# Aminoate60
84 (71 241 119-8l| -(2 4 .5 ) 5 2x10.3 600 56.5mmotes 500 ( 41. 6)
mmol

E x c ellent Ex tre m e ty High Good Good Practically Freely Moderately


low, s o l u b i l i ty insoluble soluble s o fu b l e
8.6 mg/lL
E x c ellent E x tre me l y Good;
low 86-100%
s i mi l a r
to Mg
citrate
42.3(2.961 zz.e (0.3e) 44.5 41.7 4 l oral dose ) ,
12%ionicl
l i mi tedan d
vari abl e
Sustained- Tablets, extent
Tablet Tablet Tablet Tablet
refease Tablet l V sol uti on Tablet
capsules (Maal ox)
caplets
1-2 caprets 2-4 tabs 7 tabrets, 1 Tabret 1 Tabret 2 Tablets 600 mg, Intravenous 1 Tablet ,
q 12 h T tD 3 _ b m Eq 1 tablet Mg 9.9-49.3 3 tabtets
Mg ea
mgiml ( 1 0 0m g
M inor G l Emesis, N o Gl ea Mg)
Occasional
dis t ur b- d i a rrh e a side regurgita-
ances effects tion and
mild
di arrhea
S us t ained Vi rtu a l l y Yielded a Antacid; Internal, Parenteral
r eleas e i n s o l u b l ea t greater
increases cathartic antiinfective use may
pH of Gl citraturic
absorption, tract; some responsein l eadto
r educ ess id e Gf s i d e addition to magnesium
effects; effects; primary toxicity
cathartic antacid a b s o rb a b l e
K&Ms
*Cl serumlevetVo,1.9
mg/dL.
'urinarycumulative (excretion)
*ClserumlevelVo, increment, 16.5mg/d;urinarypeakexcretion
rate,7.7 mglh.
1.63mg/dL.
.::. l:tflJ;1-hote 6toodl.s5 mmot/L;
urinarycumutartve
(xcrerion)
lcl incremsnr,
14.7smmoyd.
il?ij1*l:J[1:9x, Illn6jourgT!ore, prra,maceutrcare-,'C"rirs",ii",';lrr.

;,:,i*ljj*:**r'rTl?m;J.1';?,l'f,fl'J.1rui13*;,",,* ("-'".*ron) t,-7 dose:


,n.,",."n urinary
peak
excretion
rar6,
4.0e6
'*Urlnary cumuratrve
increment14.1 mg/d;urinaryexcreuon rcte7.2mg/h.
Gl, gastrointestinat.

as a 4-g dose, folrowed by a maintenance infusion


of r. n-1nt women/ apparent volumes of distribution
to 2 g/h by controlled infusion pump. usu_
ally reach constant values between the third
Af ter adminis tra tiory. approxima teiy 40y. of p rasma and
fourth hours after administration and. range from
magnesiuT t: protein bound. The uDound
magne. 0.250 to O.MZL/kg. Magnesium is almost exc"lusively
sium ion diffuses into the extravascular-extracellular
excreted in the urine, \ rith 90% of the dose excreted
space, into bone, across the placenta and fetal
mem_ drrring the first 24 hours after an intravenous infusion
branes, and into the fetus rr,d "*oiotic fluid. I^
frug- of magnesium sulfate. The pharmacokinetic profile
of
American lournal of Therapeutics(2007) 8(5)
354
RANADEAND SOMBERG
magnesium sulfate after intravenous administration
and oral absorption of these test compor:nds. Magne_
can be describecl by a two-compartment model with a
sium r-Iactate and aspartate have the greatest water
rapid distribution (ct) phase, iollowed by . relative
solubility, and as a result, they exhibit greater bio-
slow p phase of eliminition.
availability and oral absorption (and probibty urinary
The clinical effect and toxicity ofmagnesium sulfate
, excretion). The magnesium compound having good
can be linked to its concentration in
!lus*a. A con- availabiliry tends to possess greater serurn (p-Iaima)
centration of 1.8 to 3.0 mmol/L has been suggested.for
concentration. Magnesium salts of organic acids com-
treatment of eclamptic convtrrsions. rhe aiiual mag-
pared with those-of inorganic acids hive greater water
nesium dose and concentration needed for proph|_
solubility and therefore greater bioavallability and
laxis has never been estimated. Maternal toiicity
is oral absoqption. Among mlgnesium salts, magnesium
rare when magnesium strlfate is carefully adminis_
sulfate has been extensively studied after i't l.r"r,o*
tered and monitored- The first warning of impending
administration and its paliiative usefuLress has been
toxicity in the mother is loss of the piteuu, ieflex
ai constantly demonstrated. Magnesium surfate is
plasma concentrations between 3/5 and 5 mmol/L.
known to be moderately soluble-io uqr.r"ousprepara_
Respiratory paralysis occurs at S to d/5 mmol/L. Car_
tions. Water sotubility can be increased Uv iaminis_
diac conduction is altered at greater than 7.5 mmol/L,
tration of chelate salts of magnesium as ir, th" .ur"
and cardiac arrest can be expected when concentra-
with magnesium salicylate. Most commonly used
tions of magnesium exceed t2.5 mmor/L. Careftrl at-
magnesium salts and their biopharmaceutics data are
tention to the monito_ring guiderines can prevent tox-
summarized in the Table i.. ottrer magnesium salts not
icity. Dg"p tendon reflexes, respiratory ratl, urine
out_ as.c-omlnonly used, for example, are ialts of mandelic
put, and se*un concentrations are the most commonly
acid,phosphoric acid, silicic acid, hydrobromic acid.,
followed variables.2e
and boric acid, and these have been prepared and
several factors affect the concentration and distribu-
to possess some less significant^bioiogical ac_
tion of magnesium in patients with chronic renal fail- :l?*
tivities as well.
ure (CRF). Poor nutritional intake, impaired absorp_
tion from the intestine, vomiting, diarrhea, the use
of
diuretics, and acidosis may resirlt in a negative
bal- CLINICAL TRIALRESULTS OF
ance. More commonly, accumulation of riagnesium
may be the coruequence of reduced renar eicretion.
M A G N E S I UT
MH E R A P Y
Magnesium concentrations are increased in serum and
ln several articles,Antnan a1u131-33 reviewed exten-
RBCs in cRF patients. Bone concentrations and total
sively the pros and cons of magnesium therapy. Mug_
body magnesium also appear to be increased; muscle
nesium is a coronary and hyperemic ,uurodiiutor cal_
magnesium does not appear to be increased. Use of
hydroxide-containing antacids as phos_ 3"T antagonist,.antiarrhythrnicagent, and antiplate_
lagre.sium let drug that modulates autonomiJfunction ana'tirnits
phate binders in patients with CIRF was rargery dis-
reperfusigl hi"qf. when grvm early in the setup of
continued two decades ago after reports aesciiula in-
myocardial inJarction.Magnesitr.mbiocks calcium en-
creases in serum magnesium concentrations to toxic try into vascularsmooth muscrecels via voltage- and
levels. More recently, the undesirable effects of alumi-
receptor-operatedchannels and diminishes thl reac-
nurn-containing phosphate binders (encephalopathy,
tion of vascular smooth muscle cells to various
osteomalacia) have led several investigators to report
stimuli. Magnesium reduces the rereaseof calcium
favorable experiences using low concentrations
of folm by actually
magnesium in dialysate and combination of magne- $vi_ding calcium into the sarcoplas-
mic reticulum, and it has important erectrophysioiogic
sium and aluminum,containing antacids, u, phor_
effectsthat serve to maintain ionic balancJ"Jror, ,ur-
phate binders, while closely moiritoring ,"ru*'*ug_
colemrnalmembranes.However, magnesium also can
nesium concentrations.
induce completeheart block, cardiog-enicshock,renar
Mason3' studied saliryrate plasma revels after ad-
fgilurg, symptomatic sinus bradycariia, and hypoten_
ministration of solid dose forms of aspirin, magne-
sion. Administration of magnesinm is an inexiensive,
salirylate, and choline magnesium trisalicyiate easily administratedtherapy and its one of the advan-
:i.,*
in healthy voh:nteers. Based on this studp there were
tagesis that it canprotect_ofagainstreperf'sion injury
no significant differences in the rate and extent of ab-
by-inhibiting calcium inllux it to *yorytes and ihus
sorption of salicylate and it was not altered by these
reduce short-term mortalitv.
dose forms.
Recently-generatclinicaf ftials of magnesium ir pu_
The extent of water sorubility of magnesium salts .
tients with AMI such as the Fourth- International
appears to play an important role in the bioavailabilitv
study of Infarct survival3aand second LeicesterIntra-
Anerican lournal of Therapeutics
(2001.)B(S)
BIOAVAILA8ILITY/PHARMACOKINETICS OF MAGNESILJM
355
venous Magnesium Intervention Trial3s were con- rant an investigation for an accurate serum
ducted. The results of thesetrials have both supported
magnesium determination. tn the past, magnesium
Tl gpposed a clinically important role of magnesium may have been forgotten because the knowiedge of
MI therapy- Anknan et ar36after reviewing"the s.rb-
: other elements has been greater and were direcdy re-
ject concluded that the benefit of magnesiuri
remains lated to syndromes in crinical medicine. As our knowr-
an open question despite the large number of patients
edge about magnesium advances and technology per_
enrolled in the trials. According to e.,t*"r, ui al, aI-
rnits us to undertake rapid determinations in a"consis-
though.hypothetical arguments against the use
of tently reliable manner for the physiologically
magnesium have been raised ("g, J pression of re- active
ionized fraction or species of rrragnesiuri, the irnpor_
leasecatecholaminesfrom the adienut'gi"r,J u'.a com-
tance of magnesium in health ut d d-iseuseswili
promise of myocardial contractility), such arguments be-
c:me more apparent and magnesium replacement
outweighed by models demonstratinga ieduced I
3r9 therapy employed more frequently.
infarct size. Also clinical reports of redu"ction
of the
mortality rate when magneJium is administered dur-
ing myocardial infarction in some stud.iesis most im-
portant. However, careful selectionof the patient and R EF E RN
EC E S
dose are critical for the appropriate use of riragnesium.
Bolusesdelivered to-orJpldly may provoke f,ypot*_
sion and coronary hypoperfusion,-especially* pu- 1' RJ: Magnesium: the fifth but forgotten erectrolyte.
' r llir't
tients receiving other vasodilutors.3T Clin Chem I994;t02:61,6422.
2. Lindeman RD: Chronic renal failure and magnesium
metabolism.Magnesium 19g6;5:?93_300.
CONCLUSION 3. Wary C, Brillault-salvat C, Bloch A, et al: Effect
of
{-uonic magnesium supplementation on magnesium
knowledg.eabout magnesium absorption, ctistri_ distribution in healthy-vol'nteers evaluatediy 31p-
Yg. NMR' and ion selectiveerectrodes.Br crin phaimacol
bution, metabolism, and excretion is nelded to use J
this agent effectively. Magnesium is known to play an 1999;48:655462.
important role in conditions such as AMI, atheroscle- 4. Behar J: Magnesium absorption by th" rat ileum and
rosis,hypertension, arrhythmias, diabetesmellitus, al_ colon.Am I physiol t974;227:Jg4-..3!l0,
coholism, aldostergnism,hyperthyroidism, and renal 5. Whang R, Hampton EM, Whang DD: Magnesium ho-
tubular d.isorders.38-4s Magtiesiu; therapy, for defi- meostasisand crinicar disorders of magriesium defi-
ciency.rep-lacementand in highe, ptir*acologic ciency.Arur pharmacother L994;?S:220_?%.
doses,has been beneficial in imploving hemodynam_ 5' Gottleib ss, Fisher ML, pressel MD, et al: Effectsof in-
i"r-c6-52The role of magnesium on biochemical and travenous magnesirrm suUate on arrhythrnias in patients
cellular levels,especiallyin cardiac cells,is crucial in with congestiveheart failure.Am Heirt l99i;l?S:1646_
J
maintaining stable cardiovascularhemodynamicsand 1650.
electrophysiologic function.s3Amons th. corunon 7' Teo KK, Yusuf g Collins R, et ar: Effectsof intravenous
electrolytes,the difficurty in the accurate measure- magnesium in suspected acute myocardial infarc_
ment.of maglesium ion is well known. Furthermore, tion: overview of randomized triars. nivg tggt;s0}:1.499-
sophisticated,sensitive, and perhaps noninvasive 1503.
(avoiding muscle biopsies) tec-hniquls for assaying 8. Ceremuzynski L, Van Hao N: Ventricular arrhythmias
this cation in serum (orprasma) "t d d"termining us-- late after myocardial infarction are related to hlpo*ag_
sue levels will be availa6lefor routine use so that re- nesemiaand magnesiumross:primary trial of c'orrective
liable,-reproducible, and meaningful data can be ac, therapy. Clin Card iol t991;.t6,+ggag6.
cumulated. Ir1 the absenceof ,outine serurn magne_ 9. Whang & Oei TO, Aikawa |K, et al: predictors of ciin_
sium estimation, detection of hypokalemia rnay ical hypomagnesemia.Ann lntem Med 1964;t44:I794_
trigger an order for serum magnesiun determination 1796.
in view of the high frequency of hypermagnesemia 10. PeticoneF, CeravoloR, De Novara G, et al: New data
on
fgund in potassium-deficientpatienir. nro*lt ,".og_ the arrhythmic value of parenteral magnesium treat-
nition and treatnent of coexistinghypomagnesemiain ment, magnesiumand ventricular arrhythmias. Magnes
Res 1992;4:255-272.
hypokalemic patients can assistrn ai'oiain"gthe prob-
11. SeeligM: Cardiovascularconsequences
|1n gj patients are refractory to potassium reple. of magnesium
deficiency and loss: pathogenesrsprevare.,." *i mani-
o9r',.--rlyponatr.t., hypophosphatemia,and hypo_
festations-magnesium and chloride loss in refractorv
calcemia also are electrolyte abnormalities that war-
potassiumrepletion.Am J Med 19g9;62:4G_2I5,

American lournal of Therapeutics(2007) g(S)


356
RANADE AND SOMBERG
12. christensenCw, Riedel MA, silverstein EL, etal: Mag-
30' Mason wD: comparative prasma saricyiate and
nesium sulfatereducesmyocardialinfarct sizewhen aI- urine
salicylate levels following administr"iio. of aspirin,
ministeredprior to but not after coronaryreperfusionis
magnesium salicylate and choline magnesium trisalicy-
a caninemodel. Circulation 7995;92:ZGIT_Z6Z|.
late. J Pharm Sci 19E0;69:11355_11356.
13. Herzog W& SchlossbergML,MacMurdy RS,et al: Tim_
31' Antrnan EM: Magnesium in acute myocardial inJarction:
*g o! magnesium therapy affects experimental infarct
size. Circulation l99S;92.2622_?.626. overview of avairabre evidence. Am Heart
I r996:1,i2;
14. christensen cw, smith LM, Gao H, et ar: Apprication 487495.
of 32' Anhnan EM: Magnesium in acute MI. Circuration
a rlew nuclearscintigraphycamerato evaruaieflow and 1995;
rnechanismof artificiar hearts. ASAIO Trans r99"J.;37: 92:?357-73T2.
M50LMs05. 33. Rabbni LE, Annnan EM: The role of magnesium
therapy
15. Herzog WR, Atar D, Mak JT, et al: Magnesium in acute myocardial infarctiory Clin Carii o11996;79:g4r-
defi-
ciency prolongs myocardial stunning in in open chest M.
swine model. Int J Cardiol l99S;47:fOS_f fS. 34. ISIS-4 Collaborative Groups: ISIS-4: a randomized facto-
16. christensencw, RosenLB, Gal r(A, et al: Coronary rial trial assessing earry oral captopril, oral mononitrate
va-
sodilator reserve.C-omparisonof the effectsof papaver- and intravenous magnesium sulfate in 5g,050 patients
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