DRUG DISPOSITION Clin Pharmacokinet 2000 Apr; 38 (4): 305-314

0312-5963/00/0004-0305/$20.00/0

© Adis International Limited. All rights reserved.

Magnesium Sulfate in Eclampsia

and Pre-Eclampsia
Pharmacokinetic Principles
Jian F. Lu1,2 and Charles H. Nightingale2
1 Department of Clinical Pharmacology, Jingling Hospital, Nanjing, P.R. China
2 Pharmacy Research, Hartford Hospital, Hartford, Connecticut, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
1. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
2.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
2.2 Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
2.3 Distribution of Parenterally Administered MgSO4 . . . . . . . . . . . . . . . . . . . . . . . . . . 307
2.4 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3. Clinical Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3.1 Dosage Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3.2 Dosage and Plasma Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
4. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
4.1 Maternal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
4.2 Fetal and Neonatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.3 Drug Interactions and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.3.1 Interaction with Anaesthetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.3.2 Interaction with Nifedipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.3.3 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Abstract Magnesium sulfate (MgSO4) is the agent most commonly used for treatment
of eclampsia and prophylaxis of eclampsia in patients with severe pre-eclampsia.
It is usually given by either the intramuscular or intravenous routes. The intra-
muscular regimen is most commonly a 4g intravenous loading dose, immediately
followed by 10g intramuscularly and then by 5g intramuscularly every 4 hours
in alternating buttocks. The intravenous regimen is given as a 4g dose, followed
by a maintenance infusion of 1 to 2 g/h by controlled infusion pump.
After administration, about 40% of plasma magnesium is protein bound. The
unbound magnesium ion diffuses into the extravascular-extracellular space, into
bone, and across the placenta and fetal membranes and into the fetus and amniotic
fluid. In pregnant women, apparent volumes of distribution usually reach constant
values between the third and fourth hours after administration, and range from
0.250 to 0.442 L/kg. Magnesium is almost exclusively excreted in the urine, with
90% of the dose excreted during the first 24 hours after an intravenous infusion
306 Lu & Nightingale

of MgSO4. The pharmacokinetic profile of MgSO4 after intravenous administra-

tion can be described by a 2-compartment model with a rapid distribution (α)
phase, followed by a relative slow β phase of elimination.
The clinical effect and toxicity of MgSO4 can be linked to its concentration
in plasma. A concentration of 1.8 to 3.0 mmol/L has been suggested for treatment
of eclamptic convulsions. The actual magnesium dose and concentration needed
for prophylaxis has never been estimated. Maternal toxicity is rare when MgSO 4
is carefully administered and monitored. The first warning of impending toxicity
in the mother is loss of the patellar reflex at plasma concentrations between 3.5
and 5 mmol/L. Respiratory paralysis occurs at 5 to 6.5 mmol/L. Cardiac conduc-
tion is altered at greater than 7.5 mmol/L, and cardiac arrest can be expected when
concentrations of magnesium exceed 12.5 mmol/L. Careful attention to the mon-
itoring guidelines can prevent toxicity. Deep tendon reflexes, respiratory rate,
urine output and serum concentrations are the most commonly followed vari-
ables.
In this review, we will outline the currently available knowledge of the phar-
macokinetics of MgSO4 and its clinical usage for women with pre-eclampsia and
eclampsia.

Pre-eclampsia complicates 3 to 5% of pregnan-
cies and accounts for a considerable proportion of
morbidity and mortality during pregnancy, child-
birth and puerperium.[1-4]
Pre-eclampsia has classically been defined as
the triad of hypertension, proteinuria and oedema
occurring after 20 weeks’ gestation in a previously
normotensive woman. The nonspecific finding of
oedema has been dropped from most definitions.[5-7]
Pre-eclampsia is classified as either ‘mild’ or ‘se-
vere’. The most dangerous complication of pre-
eclampsia is eclampsia, which is defined by gen-
eral tonic-clonic convulsions before or after birth.
Although there has been no consensus about the
precise criteria to diagnose pre-eclampsia, accord-
ing to the Australasian Society for the Study of Hy-
pertension in Pregnancy pre-eclampsia is diagno-
sed as gestational hypertension and proteinuria.[6]
Gestational hypertension was defined as systolic
blood pressure of at least 140mm Hg with a >30mm
Hg rise and/or diastolic blood pressure of at least
90mm Hg with a rise of >15mm Hg occurring on
2 or more occasions after 20 weeks of gestation.
Proteinuria is defined as a urine protein concentra-
tion of at least ‘2+’ or 0.1 g/L on dipstick or 24-hour
urinary protein excretion >0.3g.
Magnesium sulfate (MgSO4) has been used for
the therapy and prophylaxis of eclampsia for well
over 70 years.[8] For eclampsia, the efficacy of mag-
nesium sulfate therapy has been well studied and
validated. Recently, the international collaborative
eclampsia trial confirmed that MgSO4 is indeed more
effective and better tolerated than alternative drugs
in the prevention and control of eclampsia.[9,10]
For pre-eclampsia, MgSO4 is often used as sei-
zure prophylaxis for severe pre-eclampsia, a use
supported by some studies.[11,12] However, the ne-
cessity for seizure prophylaxis in women with mild
pre-eclampsia has never been established in ran-
domised controlled trials. Nevertheless, there is no
consensus whether prophylactic use of MgSO4 in
pre-eclampsia does more good than harm. A large
international clinical trial (the ‘Magpie’ trial) is now
under way to address the question whether MgSO4
has any overall benefits in comparison to placebo
in the treatment of pre-eclampsia.[13]
This article focuses on the clinical pharmacoki-
netic properties of MgSO4, including its absorp-
tion, distribution and elimination, in women with
eclampsia or pre-eclampsia. The clinical usage and
toxicity of MgSO4 is also discussed.
1. Pharmacology
The mechanism by which parenteral MgSO4 pre-
vents seizures is only partially understood. Some

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2000 Apr; 38 (4)
Magnesium Sulfate in Eclampsia and Pre-Eclampsia
authors[14,15] assert that this action is mainly medi-
ated at the neuromuscular junction with minimal
central nervous system (CNS) involvement, whereas
other authors[1] believe that the main site of action
is the CNS with a minimal neuromuscular blocking
effect. This has been a source of confusion, and has
led to the development of new theories on the mode
of action of MgSO4.[16] It has been recently propo-
sed that seizures in women with pre-eclampsia are
a consequence of reduced cerebral blood flow re-
sulting from intense vasospasm and increased sen-
sitivity to pressor substances.[17,18] Women with pre-
eclampsia have intense vasospasm and increased
sensitivity to pressor substances.[19] This has led to
the proposal that seizures are a consequence of
reduced cerebral blood flow. Vasospasm in pre-
eclampsia is thought to be due to endothelial dys-
function, which in turn is believed to result from
injury mediated by free radicals. MgSO4 increases
the production of the endothelial vasodilator pro-
stacyclin.[20] Therefore, magnesium is a potent va-
sodilator, especially in the cerebral vasculature, and
the administration of MgSO4 to women with pre-
eclampsia increases brain blood flow when mea-
sured by Doppler examination of the middle cere-
bral artery.[21,22]
Currently, a possible action of MgSO4 as an N-
methyl-D-aspartate (NMDA) receptor inhibitor is
under consideration.[23-26] The NMDA receptor is
the best characterised excitatory amino acid recep-
tor subtype, and its agonists can alter neuronal ex-
citability and produce seizures. The NMDA recep-
tor has its channel blocked by magnesium ion. It
has been shown that the anticonvulsant activity of
MgSO4 may be partially mediated by blockade or
suppression of NMDA receptor activation.
2. Pharmacokinetic Profile
2.1 Absorption
MgSO4 used for eclampsia and pre-eclampsia is
most commonly given either by the intramuscular
or intravenous route using the so-called intramus-
cular regimen or intravenous regimen, respective-
ly.[27] When MgSO4 is administered intramuscu-
© Adis International Limited. All rights reserved.
307
larly, the plasma concentration shows a slow in-
crease which reaches a plateau in about 1 to 2 hours
and is followed by a slow decline back to the con-
trol level during the next 6 to 8 hours.[28] At the end
of 4 hours, when another dose of MgSO4 is injected
intramuscularly according to the intramuscular re-
gimen, the rates of absorption, distribution and ex-
cretion are about equal, and the plasma magnesium
concentration remains fairly constant.[28] Several
authors suggested that the delay in absorption [time
to maximum concentration (tmax) of 90 to 120 min-
utes] seemed clinically undesirable.[29,30] For this
reason, combining intravenous and intramuscular
injections was suggested.[30] The absorption from
the intramuscular depot balances the rapid disap-
pearance of the intravenous dose from the blood
stream. As a result, a fairly good plateau is main-
tained for 3 to 4 hours.[30]
2.2 Protein Binding
About 40% of plasma magnesium is protein bound
and is not ultrafiltrable.[31] The injected magnes-
ium is promptly bound to plasma proteins to the
same degree as that of endogenous magnesium.[31,32]
The serum ionised magnesium concentrations were
determined during intravenous MgSO4 therapy in
6 pre-eclamptic women.[32] The amount of ionised
magnesium was found to rise proportionately to
the total serum concentration of magnesium. In ad-
dition, the percentage of ionised magnesium de-
creased slightly from 64.9 ± 2.8% to 56.2 ± 2.5%
during the 6 hours of therapy. It was suggested that
the increase in the protein-bound fraction associ-
ated with higher serum concentrations of total mag-
nesium occurs because magnesium proteinate be-
haves according to the law of mass action, with a
pK of 1.77.[31]
2.3 Distribution of Parenterally
Administered MgSO4
To achieve a therapeutic concentration of mag-
nesium while avoiding potential toxicity, knowl-
edge of the volume of distribution (Vd) of magne-
sium is needed. However, the measurement of the
true magnesium space seems to be difficult. Chesley
Clin Pharmacokinet 2000 Apr; 38 (4)
308
et al.[33] calculated the apparent Vd of magnesium
in 9 women using the calibrated infusion method.[33]
After administration, the apparent Vd increases ra-
pidly and becomes constant within 2 hours in heal-
thy nonpregnant individuals. In pregnant women,
however, Vd often does not approach a constant
value until between the third and fourth hours after
administration and the values range from 0.250 to
0.442 L/kg.[33] Another study estimated the appar-
ent magnesium spaces in 4 patients.[28] The appar-
ent spaces ranged from 0.370 to 0.430 L/kg at the
end of 20 to 24 hours after administration.
The pharmacokinetic profile of MgSO4 after in-
travenous administration has been described by a
2-compartment model, with a rapid distribution (α)
phase followed by a relatively slow β phase of eli-
mination.[34,35] Wang et al.[35] investigated the phar-
macokinetic properties of MgSO4 in 20 hyperten-
sive pregnant women after fast (7.5g over 2 hours)
and slow (7.5g over 5 hours) infusion. The esti-
mated central compartment (Vc) and terminal-phase
(Vβ) volumes with a 2-compartment model were
0.250 ± 0.010 L/kg and 0.570 ± 0.022 L/kg, respec-
tively.
The distribution of magnesium in the body is
unusual.[36-38] Magnesium administered parenter-
ally is initially distributed into the intravascular com-
partment. The intravascular unbound ion diffuses
into the extravascular-extracellular space, into bone,
and across the placenta and fetal membranes and
into the fetus and amniotic fluid. There is a fairly
large amount in the cells (but none in red blood
cells) and in the extracellular phases of bone; there
is, however, only a small quantity in the extracellular
fluid. Only that part of magnesium present in the
extracellular compartment, as measured by plasma
or serum concentrations of magnesium, is available
for study.
A great deal of work has been done on the de-
termination of magnesium concentration in the cere-
brospinal fluid, breast milk/colostrum and fetus.
The mean baseline CSF magnesium level for pre-
eclamptic patients is 1.1 ± 0.05 mmol/L, which is not
significantly different from that in controls, and there
is no correlation between cerebrospinal fluid and se-
© Adis International Limited. All rights reserved.
Lu & Nightingale
rum magnesium levels over the range of baseline
values.[39] Two studies have examined CSF mag-
nesium in pre-eclampsia after infusion of magnes-
ium.[28,40] In spite of the similar value of CSF mag-
nesium, opposite conclusions were reached in these
studies. Pritchard et al.[28] compared healthy un-
treated pregnant women to pre-eclamptic patients
after intramuscular injection of MgSO4 and conclu-
ded that CSF magnesium must be almost totally
independent of maternal plasma concentrations. Thu-
rnau et al.[40] concluded that there was a small but
significant difference in CSF magnesium concen-
trations between the two groups. Animal studies
have confirmed that isotopically labelled magne-
sium enters the CSF rapidly and was equilibrated
within 2 to 3 hours.[41]
Magnesium ions cross the placenta and are rap-
idly taken up by fetal tissues.[42] Thus, magnesium
in amniotic fluid, the fetus and in neonates of moth-
ers treated with MgSO4 show increased concentra-
tions compared with untreated mothers. The paren-
teral administration of MgSO4 to both healthy and
pre-eclampsia women results in a delayed increase
in fetal plasma magnesium concentrations which
ultimately equals the maternal rise.[28,43] The aver-
age delay in the establishment of equilibrium be-
tween maternal and fetal plasma is about 2 hours.
The increase in amniotic fluid magnesium concen-
tration occurs more slowly than in fetal plasma and
is more variable. Following prolonged therapy, the
magnesium concentration in the amniotic fluid is
significantly higher than the maternal plasma con-
centration.[28] Hypermagnesaemia has been found
to develop in full term appropriate growth neonates
exposed to maternal MgSO4 therapy.[1,44] When the
mother receives MgSO4 infusions of 1 to 2 g/h,
fetal serum magnesium concentrations are twice as
high as control concentrations, and the highest con-
centrations observed are in umbilical venous and
arterial blood. By 48 hours after birth, significant
difference between treated and control neonates is
no longer demonstrable.[43]
The amount of magnesium excreted in breast
milk also has been determined.[44] During the first
24 hours after intravenous infusion of MgSO4, about
Clin Pharmacokinet 2000 Apr; 38 (4)
Magnesium Sulfate in Eclampsia and Pre-Eclampsia
1.5mg of magnesium was present in breast milk;
this amount, although small, is significantly higher
than that in the breast milk of control patients. On
the second post-infusion day, there was no signif-
icant difference, and by the third day, the amount
was almost identical. Mothers who want to nurse
and are medically stable may be allowed to do so
after magnesium therapy without danger to the new-
born.[44]
2.4 Elimination
MgSO4 is not metabolised and is excreted by the
maternal kidney, which represents the sole route of
elimination.[1] Urinary excretion is very rapid and
increases 20-fold during MgSO4 infusion.[45] At the
end of 4 hours, from 38 to 53% (average 44%) of
the total injected magnesium has been excreted.[33]
By 24 hours after the infusion more than 90% has
been eliminated.[28,45] In patients with normal renal
function, the magnesium clearance increased as a
roughly linear function of the serum magnesium
concentration.[31] Once all extracellular fluid mag-
nesium concentrations have reached equilibrium
with serum, the rate of urinary magnesium excre-
tion equals the rate of infusion, and the 24-hour
excretion of magnesium is almost equal to the am-
ount administered.[45] However, patients with im-
paired renal function can develop hypermagnesae-
mia with these doses, which usually occurs when
the patients’ urinary flow is less than 100 ml/4h.[28]
The half-life of MgSO4 in patients with normal
renal function is 4 hours; if the glomerular filtration
rate is decreased, the half-life increases.[21] The elim-
ination half-life (t1⁄2β) estimated with a 2-compart-
mental model was 4.04 ± 1.94 hours in 20 pregnant
woman after intravenous infusion of MgSO4 with
fast (7.5g in 1 hour) and slow (7.5g in 5 hours)
infusion rates.[37] The half-life (t1⁄2ke) estimated us-
ing a 1-compartmental model was reported to be
3.66 ± 1.97 hours in another 30 patients with preg-
nancy-related hypertension receiving the same do-
sage regimen.[46]
MgSO4 therapy influences the rate of excretion
of calcium. Urinary calcium concentration increa-
ses 4.5-fold during MgSO4 infusion, and the uri-
© Adis International Limited. All rights reserved.
309
nary calcium excretion rate is 3 times that observed
in controls.[45] Chesly and Tepper[31] found an 8- to
20-fold increase in urinary calcium concentration
after infusion of magnesium. The most likely ex-
planation for the increased urinary calcium excre-
tion is that magnesium and calcium compete for
common reabsorption sites. In the kidney, unbound
plasma magnesium is filtered by the glomerulus
and reabsorbed in the tubules. The fraction of mag-
nesium reabsorbed is indirectly proportional to the
serum magnesium concentration. Thus, the increa-
sed filtered load of magnesium leads to increased
tubular reabsorption of magnesium and the compe-
tition for reabsorption sites leads to increased uri-
nary calcium loss.[47]
The concentration of magnesium attained in
plasma after parenteral administration of a given
dose depends upon the Vd and renal excretion of
the magnesium. In the presence of severe oliguria
or advanced renal failure, the Vd determines the
concentration.[28] However, with normal renal ex-
cretion, the renal clearance rate of magnesium is
the primary determinant of the serum magnesium
concentration, with body size and Vd playing a mi-
nor role once a steady state is reached.[31] In addi-
tion, it has been demonstrated that the maximal serum
concentration of magnesium during therapy dep-
ends on the rate of infusion and not on the total
dose given or the duration of infusion after the pla-
teau has been reached.[48]
3. Clinical Usage
3.1 Dosage Regimens
MgSO4 has been used therapeutically as an an-
ticonvulsant and tocolytic agent in the treatment of
eclampsia and inhibition of preterm labour, respec-
tively.[49] MgSO4 has also found use as an antiar-
rhythmic agent[50] as well as an osmotic cathar-
tic.[51]
Since the application of MgSO4 for the treat-
ment of severe pre-eclampsia and eclampsia, vari-
ous regimens and methods for administration of
the drug have been devised. There is no consensus
on the appropriate dosage and concentration of
Clin Pharmacokinet 2000 Apr; 38 (4)
310
MgSO4 required for therapeutic efficacy. Current-
ly, the 2 most widely used schedules of MgSO4 are
the intramuscularly administered regimen popular-
ised by Pritchard[28] and the continuous intraven-
ous regimen recommended by Zuspan.[52] Both re-
gimens have become standard treatment over 30
years and are associated with dramatic reduction in
maternal and neonatal morbidity related to eclamp-
sia.
The intramuscular regimen is most commonly
given as a 4g intravenous loading dose, followed
by 10g intramuscularly and then by 5g intramuscu-
larly every 4 hours in alternating buttocks. The in-
travenous regimen is given as 4g intravenously, fo-
llowed by a maintenance infusion of 1 to 2 g/h by
controlled infusion pump. These are known as Prit-
chard’s and Zuspan’s regimens, respectively.
Nevertheless, controversies remain, particularly
about the optimum dose required for maintenance
infusion. There is no evidence from the collabora-
tive trial[9] of any difference between the intramus-
cular and intravenous regimens in their effects on
recurrent convulsions. However, intramuscular in-
jections are painful and are complicated by local
abscess formation in 0.5% of cases. The intrave-
nous route is therefore preferred. However, the in-
tramuscular regimen becomes the better option when
intravenous infusion pumps are not available, con-
tinuous monitoring is not feasible, or when the pa-
tient must be transferred to another facility.
Therapeutic concentrations are consistently achie-
ved after an intravenous loading dose of 4g (given
over 15 minutes). If the woman is convulsing or has
recurrent convulsions, it is recommended that a bolus
of 2 to 4g should be given over 5 minutes.
It is important that in the administration of MgSO4
by any of these schedules, certain clinical observa-
tions should be made before each injection: (i) deep
tendon reflexes must be present; (ii) respiration must
be at least 16/minute; and (iii) 100 ml of urine must
have been excreted since the preceding injection.
In addition, 1g of calcium gluconate should be av-
ailable as an antidote for hypermagnesaemia.
© Adis International Limited. All rights reserved.
Lu & Nightingale
3.2 Dosage and Plasma Concentrations
Pritchard[53] noted that higher concentrations of
magnesium were needed for arrest of convulsions
rather than for seizure prophylaxis. The concentra-
tions suggested by Pritchard for prophylaxis, how-
ever, were similar to those used for seizure therapy
(1.8 to 3.0 mmol/L).[53] Reports from other authors
suggest that the concentrations may be lower than
those recommended by Pritchard.[48] In general, the
therapeutic concentration is considered to be be-
tween 2 and 4 mmol/L. However, this is based on
clinical experience and not directly related to the
suppression of eclamptic convulsions.
An intravenous loading dose of 4g to 6g results
in an immediate but transient increase in plasma
concentrations to 2.1 to 3.8 mmol/L, which decli-
nes to 1.3 to 1.7 mmol/L within 60 minutes.[53] A
delay in the peak concentration was noted by Ches-
ley,[33] who found the average tmax to be 60 minutes
after intramuscular injection. At a constant infusion
rate, serum concentrations reach a plateau when the
rate of urinary excretion of magnesium equals the
rate of infusion.[48] With an infusion of 1 g/h, MgSO4
concentrations reach a plateau after 24 hours at a
concentration of 1.7 mmol/L; an infusion rate of
2 g/h yields a steady-state concentration of 2.2
mmol/L at 6 to 8 hours.[48,53]
Sibai et al.[54] compared the magnesium concen-
trations obtained in the treatment of pre-eclamptic
patients with the intramuscular regimen to the con-
centrations obtained with continuous intravenous
regimens using maintenance doses of 1 g/h and 2
g/h. Figure 1a summarises the mean ± SD maternal
magnesium concentrations achieved in patients re-
ceiving the intravenous regimen (4g intravenous
loading dose, followed by maintenance infusion of
1 or 2 g/h). Figure 1b depicts the mean ± SD ma-
ternal magnesium concentrations achieved in pati-
ents receiving the intramuscular regimen. For sev-
ere pre-eclampsia in the study, patients were given
4g intravenous loading dose, followed 10g intra-
muscular and then by 5g intramuscularly every 4
hours. Patients with mild pre-eclampsia in the study
received a similar protocol, but the intravenous load-
ing dose was omitted. It is important to note that
Clin Pharmacokinet 2000 Apr; 38 (4)
Magnesium Sulfate in Eclampsia and Pre-Eclampsia 311

a when a MgSO4 maintenance dosage of 1 g/h was

7
used in the intravenous regimen, the mean magne-
sium concentration was <1.7 mmol/L (<4 mg/dl),
which is below the therapeutic range (2 to 4 mmol/L).
6 In addition, it was found that the intramuscular reg-
imen (Pritchard’s) achieved higher serum concen-
trations in the first 3 hours than the intravenous
5
regimen (Zuspan’s) when a 2 g/h maintenance in-
fusion was used. The initial difference may be ex-
plained by increased retention of magnesium after
intramuscular administration, which has a higher
4
initial dose compared with the intravenous regi-
men. Because of the difference in serum concen-
trations during the first 3 hours, Sibai et al.[54] sug-
3 gested to increase the intravenous infusion rate to
3 g/h initially with careful monitoring to avoid tox-
Serum magnesium (mg/dl)

2g/h (n = 7)
1g/h (n = 7) icity. However, the benefit and safety of higher dose
MgSO4 has not yet been investigated.
2
0 1 2 3 4 5 10 20

b 4. Toxicity
8

4.1 Maternal Toxicity

7 The overall tolerability and efficacy of MgSO4

in term-gestation eclampsia are well established.[9]
Therefore, maternal toxicity is rare when MgSO4
6
is carefully administered and monitored. The ad-
verse effects of the drug, which are minimally
life-threatening, include flushing, increased warmth,
headaches, blurred vision, nausea, nystagmus, leth-
5 argy, hypothermia, urinary retention and faecal im-
paction (usually at 3.8 to 5 mmol/L).[55] In the ma-
jority of patients, these adverse effects are transient
4 and mild. Several investigators have related the
pharmacological and toxic effects of magnesium to
its concentration in plasma. The first warning of
3 impending toxicity in the mother is loss of the pa-
tellar reflex at plasma concentrations between 3.5
Severe (n = 8) to 5 mmol/L. Respiratory paralysis occurs at 5 to 6.5
Mild (n = 10)
2
mmol/L.[56] Cardiac conduction is altered at grea-
0 2 4 6 8 10 12 ter than 7.5 mmol/L, and cardiac arrest can be ex-
Time (h) pected when concentrations of magnesium exceed
Fig. 1. Serum magnesium concentrations in patients receiving 12.5 mmol/L.[57]
intravenous regimens (a) and receiving intramuscular regimens
for mild and severe eclampsia (b). Note that concentrations are
Careful attention to the monitoring guidelines
expressed in mg/dl; to convert to mmol/L as used in the text, can prevent toxicity. Deep tendon reflexes, respi-
divide by 2.43 (reproduced from Sibai et al.,[54] with permission). ratory rate, urine output and serum concentrations

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2000 Apr; 38 (4)
312
are the most commonly followed variables. At the
therapeutic serum magnesium concentration of 2 to
3.5 mmol/L, deep tendon reflexes may be hypoac-
tive but remain present. If deep tendon reflexes are
present, magnesium concentrations are rarely toxic.
Urine output should be at least 100 ml/4h. Oliguria
can indicate deteriorating renal function and can
cause magnesium toxicity, because magnesium is
excreted predominantly in the urine.
Another less common but serious maternal ad-
verse effect is hypocalcaemia.[58,59] Although usu-
ally mild, serum calcium levels of <7 mg/dl are not
rare and can lead to maternal seizures. Whether one
should treat the hypocalcaemia, and at which level
to treat, is poorly studied.
4.2 Fetal and Neonatal Toxicity
Magnesium can readily crosses the placenta, and
the fetus is not immune to potential effects, bene-
ficial or harmful.
Lipsitz and English[60] reported respiratory de-
pression and hyporeflexia in a small group of new-
born infants of mothers treated with intravenous
MgSO4. Stone and Pritchard[61] subsequently pre-
sented extensive observations made at Parkland Me-
morial Hospital that did not support the contention
of Lipsitz and English that magnesium therapy com-
monly leads to neonatal respiratory depression.
In a retrospective epidemiological study, Nelson
and Grether[62] reported that prenatal magnesium
administration may reduce the risk of cerebral pal-
sy for very low birthweight babies. However, fur-
ther epidemiological work produced conflicting res-
ults.[63,64] Most studies found no cerebroprotective
effect. In one clinical trial, interim analysis showed
that MgSO4 given to mothers in preterm labour be-
fore 34 weeks is associated with a significant in-
crease in neonatal mortality.[65] Whatever the true
effects for these low birthweight preterm babies,
reassurance is also required about the short and long
term effects of in utero exposure to MgSO4 on term
babies.[13]
© Adis International Limited. All rights reserved.
Lu & Nightingale
4.3 Drug Interactions and Contraindications
4.3.1 Interaction with Anaesthetic Agents
On some occasions, the anaesthetist may be faced
with a patient treated with MgSO4 undergoing gen-
eral anaesthesia. Magnesium, however, has been
shown to potentiate the activity of both depolaris-
ing and nondepolarising neuromuscular blocking
agents.[66] Magnesium does not appear to prolong
the duration of action of suxamethonium chloride,
but the interaction between magnesium and the non-
depolarising relaxants must be borne in mind. If
this combination is to be used, then the dosage of
relaxant should be reduced.[67] The vasodilator pro-
perties of MgSO4 could theoretically increase the
risk of maternal hypotension with epidural anaesth-
esia, but anecdotal evidence over decades suggests
that anaesthetists have successfully given epidural
anaesthesia without problems to pre-eclamptic wo-
men who are receiving MgSO4 for seizure prophy-
laxis. Vincent et al.[68] showed that the infusion of
MgSO4 slightly decreases maternal blood pressure
during epidural lidocaine anaesthesia; however, there
is no decrease in uterine artery blood flow or fetal
oxygenation.
4.3.2 Interaction with Nifedipine
Occasionally a patient is simultaneously expo-
sed to MgSO4 and nifedipine; because both agents
are calcium antagonists, some interaction might be
expected. A depressive effect on blood pressure (in-
creased hypotensive effect) has been observed when
these agents are combined.[69] Fenakel et al.[70] stud-
ied nifedipine in women who were receiving MgSO4
and found effective blood pressure control in 96%
of women without undesirable adverse effects and
no case of hypotension in 24 cases studied. It would
therefore appear that while a theoretical risk of in-
teraction does exist, in practice this may be rela-
tively uncommon.
4.3.3 Contraindications
To prevent toxicity of MgSO4, cognisance should
be taken of some of its contraindications, which
include impaired renal function and history of mild
cardiac ischaemia. Caution should also be kept in
Clin Pharmacokinet 2000 Apr; 38 (4)
Magnesium Sulfate in Eclampsia and Pre-Eclampsia
mind when MgSO4 is taken with a calcium antag-
onist or anaesthetic agent.
5. Conclusion
MgSO4 will certainly remain a commonly used
agent for the management of eclampsia. Although
its mechanism of action remains elusive, the phar-
macokinetic properties in women with eclampsia
and pre-eclampsia are relatively clear. Specifically,
after administration, the magnesium ion diffuses
into the extravascular-extracellular space, into bone,
and across the placenta and fetal membranes and
into the fetus and amniotic fluid. Magnesium is
almost exclusively excreted in the urine, with 90%
of the dose excreted by 24 hours after the infusion.
The half-life in patient with normal renal function
is 4 hours.
The administration of magnesium for eclampsia
and pre-eclampsia commonly follows the so-called
Pritchard’s and Zuspan’s regimens. From the view-
point of pharmacokinetics, a maintenance dosage
of 2g/h should be used in Zuspan’s (intravenous)
regimen to target the therapeutic concentration of
2 to 4 mmol/L revealed through the clinical expe-
rience reported by Pritchard. An initial mainten-
ance dosage of 3 g/h in the intravenous regimen has
also been suggested to overcome the lower concen-
tration in the first 3 hours compared with the intra-
muscular regimen. However, there is still no clear
demonstration of whether high dosage regimens
are more effective without increasing toxicity. With
diligent clinical monitoring of deep tendon reflex-
es, respiratory rate, urine output and serum concen-
trations, MgSO4 is well tolerated and beneficial in
treatment of eclampsia for both mother and infant.
Acknowledgements
The authors would like to thank Xiaomei Cao and Jinqiu
Xu for their assistance in preparing the manuscript, and Dr
Cyprian O. Onyeji for his review.
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Correspondence and offprints: Dr Jian F. Lu, C255, NON-
MEM Group, University of California at San Francisco, San
Francisco, CA 94143-0626, USA.
E-mail: jianfeng@c255.ucsf.edu
Clin Pharmacokinet 2000 Apr; 38 (4)