ARTICLE
Auteur(s) : Jean Durlach1, Andrée
Guiet-Bara2, Nicole Pagès3, Pierre
Bac4, Michel
Bara2
1SDRM, 64 rue de Lonchamp, 92200 Neuilly,
France
2Laboratoire de physiologie et physiopathologie,
Université P. et M. Curie, Paris, France
3Laboratoire de toxicologie, Faculté de pharmacie,
Université Louis Pasteur, Strasbourg,
67400 Illkirch-Grafenstaden, France
4Laboratoire de pharmacologie, Faculté de pharmacie,
Paris XI, Pierre Maurois, 92290 Chatenay-Malabry,
France
Magnesium ions are known to play a central role in cellular
function and to strongly influence the cardiovascular and
neuromuscular excitability. They are also an important factor in
both the growth and maintenance of living cells and an essential
co-factor for many intracellular enzymes involved in both
glycolytic metabolism and ion movements mediated by Na and Ca pumps
[1]. Magnesium sulphate (MgSO4, 7H2O) is
commonly used, in the United States, as prophylactic and clinical
treatment of eclamptic seizures whereas in Europe, its use is
highly debated in that indication. Conversely, magnesium chloride
is not frequently used in either physiology or physiopathology.
Nonetheless, it has been postulated, but not established, that the
anion associated with magnesium other than sulphate could have a
less toxic, or even beneficial effects on neonate health
outcomes.Several scholarly reviews have concluded that
MgSO4 was not an effective tocolytic agent, and have
recommended to ban it in that indication [2]. Nevertheless, in
spite of the lack of supporting data and the ongoing absence of an
international consensus, MgSO4 remains the first line
pharmacological agent employed for tocolysis in North America.
Finally, it seems that the large clinical use of MgSO4
results more from routine habits than from clinical,
pharmacological or toxicological data. However, other magnesium
compounds such as oxide, gluconate and chloride may be successfully
used in various pathological situations. For example, these
magnesium salts are effective in promoting continued uterine
quiescence in patients recently treated for preterm labor [2]. In
addition they are generally less toxic than MgSO4.All
these considerations led us to highlight the differences between
the pharmacological and toxicological properties of
MgSO4 and MgCl2. MgSO4 has the
least interesting properties. Its absorption, cellular penetration,
membrane effects and antihypoxic properties are low. Comparative
studies between MgSO4 and MgCl2 have shown
that absorption and retention are more efficient with
MgCl2 than with MgSO4[3].Consequently, the
aim of the present review was to compare the properties and the
effects of both magnesium sulphate and chloride.
Physical comparison
The main physical and chemical properties of each magnesium salts
are summarized in the table 1( Table 1
).
Table 1 Comparison of each magnesium salts
properties.
|
Magnesium salts
|
|
|
|
Elemental Mg++/dose (mg)
|
25.54
|
20.2
|
|
Solubility in water
|
- 1 g dissolves in:
- - 0.6 ml water
- - 0.3 ml boiling water
- - 2 ml alcohol
|
- 1g dissolves in:
- - 0.8 ml water
- - 0.2 ml boiling water
- - slightly in alcohol
|
|
Density
|
1.56
|
1.67
|
|
Bioavailability
|
good
|
low
|
|
Oral absorption % (mEq)
|
19.68 (1.04)
|
4 (oral dose), limited and variable extent
|
|
H2O molecules lost at 100°C
|
2
|
5
|
|
Lethal doses (LD 50) (i.v.)
|
176 mg/kg (rats)
|
750 mg/kg (dogs)
|
Examples of physiological and clinical utilisation of
MgSO4 and MgCl2
Some recent MgSO4 and MgCl2 uses are reported
hereafter.
Magnesium sulphate alone
In the last decade, many papers were published, dealing with
MgSO4 uses. They may be classified as clinical and
pharmacological data.
Pharmacological uses
- – MgSO4 shows vaso- and neuro-protective
properties after spinal cord injury [4];
- – Postnatal MgSO4 infusion is safe and can
improve short-term outcome in infants with severe birth asphyxia
[5];
- – MgSO4 has an effective antithrombotic
activity in vivo, and treatment with MgSO4 may lower the
risk of thromboembolic-related disorders [6];
- – MgSO4 is an effective and safe
antiarrhythmic agent for arrhythmias developed after open-heart
surgery. Its antiarrhythmic effect may be related to its
pharmacological properties and not to the normalization of the
circulating magnesium concentrations [7];
- – MgSO4 is given in cardioplegia [8];
- – The mitochondrial respiratory function which decreases
significantly after traumatic brain injury can be improved after
MgSO4 infusion as shown by electron microscopy [9];
- – A beneficial effect of MgSO4 has been also
reported after severe traumatic brain injury in rats [10].
Clinical uses
- – First of all, MgSO4 has been often used in
case of preeclamptic-eclamptic seizures [11-13] but it has been
also successfully used in other clinical indications, as reported
hereafter.
- – MgSO4 may be beneficial in the control of
ventricular ectopy and supraventricular tachyarrhythmias after
coronary artery bypass graft surgery [14];
- – MgSO4 is used clinically to induce smooth
muscle relaxation, mainly in airway smooth muscles [15];
- – MgSO4 administration may lead to a
significant reduction of anaesthetic drugs during total intravenous
anaesthesia with propofol, remifentanil and vecuronium [16-17]. In
addition, the intraoperative use of MgSO4 as an adjunct
to the conventional use of nicardipine has been effective to manage
a pediatric patient undergoing a laparoscopic operation [18];
- – MgSO4 may be considered as an alternative
treatment in persistent pulmonary hypertension of the newborn when
no other modalities exist since it is a non aggressive and low cost
treatment [15].
Magnesium chloride clinical uses
MgCl2 has been used less frequently. However, its
usefulness was reported in various indications.
- – MgCl2 is an efficient anaesthetic and
narcotic agent for cephalopod molluscs [19];
- – It has a valuable role as cardioprotective agent in
rabbits [20];
- – MgCl2 is a more advisable salt to use in
cerebral palsy [21];
- – Oral supplementation with MgCl2 solution
restored serum magnesium levels, improving insulin sensitivity and
metabolic control of type 2 diabetic patients with decreased serum
magnesium levels [22].
Consequently, it appears very interesting to review, in the
literature, the studies comparing the respective effects of
MgSO4 and MgCl2, the magnesium salt which has
the best fits with MgSO4 in regard to elemental
Mg++/dose (in mEq).
Comparison between magnesium chloride and magnesium
sulphate
The publications comparing the two magnesium salts are very scarce
but allow to distinguish similar and proper effects to each
magnesium salt.
Similar effects
In the literature, there are some examples of similar
pharmacological and clinical effects between MgCl2 and
MgSO4.
Pharmacological effects
- – The comparison of the muscle relaxant activity of
equimolar solutions of MgCl2 and MgSO4 using
the head drop method in rabbits shows no statistical difference
between the two salts with regard to their potency and duration of
action, suggesting that these activities are not influenced by the
anion associated with the Mg2+ cation [23];
- – No significant difference was seen between
MgCl2 and MgSO4 infusions on the duration of
epinephrine-induced cardiac arrhythmia [24];
- – The two salts decrease the aldosterone production in a
dose-dependent manner [25];
- – MgCl2 and MgSO4 have similar
effects on the isolated and perfused rat heart: decreasing heart
rate, left ventricular systolic pressure, voltage epicardial
electrogram and increasing coronary flow rate [26];
- – MgCl2 or MgSO4 treatments are
equally effective on diffuse axonal injury [27].
Clinical effects
- – Both salts have a similar oral tocolytic role [28].
Compared with MgSO4 and ritodrine, enteric-coated
MgCl2 was as effective in prolonging pregnancy and
preventing recurrent preterm labor.
- – MgCl2 and MgSO4 penetrate the
blood-brain barrier after brain damage, enter injured tissue and
improve neurologic outcomes [29].
These results demonstrate the possible use of MgCl2
instead of MgSO4 and reciprocally in pharmacological and
clinical indications.
Different effects
Some recent studies indicate different or/opposite effects between
MgCl2 and MgSO4.
MgSO4 > MgCl2
- – The poliovirus and measles vaccines [30] are
stabilized by incorporating molar MgCl2 or
MgSO4 respectively. The MgCl2-stabilized
poliovirus vaccine loses 0.5 log10 units in three hours at 45°C
whereas MgSO4-stabilized measles vaccine loses only 0.3
log10 in 30 minutes at 50°C.
- – The effect of precalving magnesium source (MgO,
MgSO4 and MgCl2) and post calving calcium
supplementation were examined on calcemia and calciuria:
postcalving plasma calcium concentration was affected by precalving
magnesium source with MgSO4 > MgCl2 >
MgO sequence [31].
MgCl2 > MgSO4
- – Nishio et al. [32] studied the influence of magnesium
salts (MgCl2, MgSO4, Mg aspartate HCl and Mg
acetate) on rat mesenteric arteriole and venule reactivity to
standard constrictor doses of epinephrine and BaCl2 and
showed that arteriolar constrictions were attenuated by systemic
intravenous infusion of each Mg salt tested, except
MgSO4 which was insufficient.
- – Grin et al. [33] studied, in dogs fed a normal diet,
the antiarrhythmic and proarrythmic effects of MgCl2 and
MgSO4 intravenous infusions and showed that infusion of
MgSO4 solution decreased plasma sodium, potassium and
ventricular fibrillation threshold (VFT) (a proarrhythmic effect),
prolonged the ventricular effective refractory period (VERP) and
increased the urinary excretion of potassium. By contrast, infusion
of MgCl2 solution did not affect VFT and plasma
potassium levels and prolonged also VERP.
- – Durlach et al. [3] have pointed out that
MgCl2 was both more effective and less toxic than
MgSO4 in maintaining optimal aquaculture of scallops.
From these data, they have indicated that MgCl2 had a
better “therapeutic ratio” (LD50/ED50) than MgSO4, which
could be relevant even in human beings. Such data raised the
question as to whether the magnesium cation might be responsible
for MgSO4 toxicity or if such toxicity was instead
attributable to the associated sulphate anion.
The reason of the toxicity of magnesium pharmacological doses of
magnesium using the sulphate anion rather than the chloride anion
may perhaps arise from the respective chemical structures of both
the two magnesium salts. Chemically, both MgSO4 and
MgCl2 are hexa-aqueous complexes. However
MgCl2 crystals consist of dianions with magnesium
coordinated to the six water molecules as a complex,
[Mg(H2O)6]2+ and two independent
chloride anions, Cl-. In MgSO4, a seventh
water molecule is associated with the sulphate anion,
[Mg(H2O)6]2 +[SO4.
H2O]. Consequently, the more hydrated MgSO4
molecule may have chemical interactions with paracellular
components, rather than with cellular components, presumably
potentiating toxic manifestations while reducing therapeutic effect
[11].
Finally, to corroborate these explanations, two experimental in
vitro studies in the physiology of human gestational physiology –
amniotic membrane and allantochorial placental vessels – must be
considered. Since 1984, the research group associating M. Bara, A.
Guiet-Bara and J. Durlach has studied the interrelation between Mg
salts and various elements of the placental unit [34-41].
– Human amniotic membrane [34-37]
These experiments associated electrophysiological and morphological
studies. The main results were as follows.
- – Scanning and transmission electron microscopy results,
analysed by a stereological method which indicates the ratio
between the volume of the intercellular space (R1), the microvilli
(R2) and the podocytes (R3) versus the cell volume, showed that (i)
at low concentration, MgSO4 increased R1 and R2 but
decreased R3, whereas MgCl2 decreased R1 and R3 and had
no significant effect on R2; (ii) at high concentration,
MgCl2 decreased R1 and increased R2 and R3, while
MgSO4 had no significant effect on R1, increased R2 and
decreased R3 [34].
- – The study of the ionic fluxes in the two directions
between the mother and the fetus indicated that, when the
MgCl2 concentration increased, the ratio between influx
and efflux being was two-fold increased, whereas when the
MgSO4 concentration increased, influx and efflux became
equal. Consequently, MgSO4 could not guarantee the fetal
needs in sodium and potassium provided across the human amnion
[35].
- – In addition, it has been demonstrated that
MgCl2 interacts with all the exchangers in the membrane,
while the effect of MgSO4 effect is limited to
paracellular components without interaction with cellular
components, with exception of the antiport Na/H [36, 37].
To sum up, MgCl2 interacts with all exchangers while
the interaction of MgSO4 is limited to paracellular
exchangers, and MgCl2 increases the flux ratio between
mother to fetus while MgSO4 decreases it.
– Human allantochorial placental vessels [38-42]
- – MgCl2 or MgSO4 added in vitro
induced a depolarization of the human placental chorionic cells
(from arteries and veins with or without endothelium), but the
depolarization thresholds were different and higher with
MgSO4. This difference indicated that MgCl2
influences the cell membrane potential directly, whereas
MgSO4 interferes first with endothelial cells and then
with muscle cells [38, 39].
- – MgCl2 and MgSO4 both regulated
the cell tonus and the Ca2+ influx through voltage-gated
Ca2+ channels in smooth muscle and endothelial cells but
the depolarization reduction was more important with
MgCl2 than with MgSO4[40].
- – Moreover, MgCl2 blocked the ATP-dependent
K+ channels and opened the delayed (K(df)) K+
channels, while MgSO4 blocked the current through
voltage-gated and ATP dependent K+ channels but had no
effect on K(df) [41]. These results were confirmed by
micro-particle induced X-ray emission studies [42].
To sum up, the differences between MgCl2 and
MgSO4 were less important in allantochorial vessels than
in amniotic membranes, but the effects of MgCl2 effects
seemed more interesting than those of MgSO4 ones.
The comparison reveals that it is very difficult to reach a
conclude conclusion on the possible utilisation of a one salt
instead of another but it indicates that MgSO4 is not
always the appropriate salt in clinical therapeutics and that
MgCl2 seems the better anion-cation association to be
used in many clinical and pharmacological indications.
Conclusions
This review showed shows that it is difficult to elicit identify
MgSO4 or MgCl2 as the reference magnesium
salt to be used as a therapeutic agent, since each salt displayed
valuable clinical properties in various cases situations. The
comparison did not allow to a preference of one salt to over the
another other, but the studies indicated that MgSO4 is
not the alone only magnesium salt which may be used in severe
injuries.
It is attractive tempting to explain the differences between
MgCl2 and MgSO4 by their crystal structures.
Magnesium chloride forms a stable hexahydrate, while magnesium
sulphate forms a stable heptahydrate [43]. In the two crystals,
magnesium has the same complex form. Consequently, the different
effects observed might be attributed to the anions. As a result,
the biological properties of magnesium salts might depend on their
interactions with water and with the polar groups at the membrane
surface by screening and/or binding processes [44].
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