Response to 20mmol of magnesium sulfate

 
This chapter is somewhat relevant to Section I1(iii) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "describe the distribution, regulation and physiological importance of sodium, chloride, potassium, magnesium, calcium, and phosphate ions". The subject of magnesium pharmacology, which comes up often in the CICM First Part exam, seemed like a good excuse to discuss the physiological effects of infusing two ampoules of concentrated magnesium sulfate into a patient. 

These questions have largely called for a pharmacology-like template:

Class Electrolyte replacement
Chemistry Divalent cation salt
Routes of administration IV, orally, or as a neb
Absorption 30% oral bioavailability (depends on body magnesium levels - more is absorbed in states of systemic magnesium depletion)
Solubility pKa -3.0; good water solubility
Distribution VOD =0.25-0.442 L/kg; 40% protein-bound
Target receptor Numerous pharmacodynamic targets, including NMDA receptors, L-type calcium channels,
Metabolism Not metabolised, but is a cofactor in numerous metabolic processes
Elimination Renally excreted; reabsorption mainly by thick ascending lmb and distal convoluted tubule. Supraphysiological plasma concentrations result in decreased reabsorption
Time course of action Half life of around 4 hours
Mechanism of action Multiple mechanisms of action, including:
- Smooth muscle relaxation by increasing the uptake of intracellular calcium into the sarcoplasmic reticulum
- skeletal muscle relaxation due to inhibition of acetylcholine release from the neuromuscular junction
- CNS depressant effects by inhibition of NMDA receptors
- Decreased AV node conduction due to calcium channel blocker effects
- co-factor in electrolyte homeostasis, including Na+/K+ ATPase function
 
Clinical effects Bronchodilation, areflexia, muscle weakness, smooth muscle relaxation, vasodilation, anticonvulsant effects,
Single best reference for further information Connolly & Worthley (1999)

A vast amount of magnesium-flavoured literature awaits the curious reader. For the purpose of exam preparation, the CICM exam candidate should probably read something by CICM, such as this 1999 paper by Connolly & Worthley (of whom the latter is suspected of having written the vast majority of CICM exam questions from the early noughties). Additionally,  this entry from StatPearls is especially good for the physiological effects of magnesium, which are clearly listed in the end.

Pharmacokinetics of magnesium sulfate

Presentation and administration

These 2 ampoules of magnesium sulfate contain 20mmol of magnesium (Mg2+) and 20mmol of sulfate (SO4-) ions, i.e each contain 5ml of water, and 10 mmol each of magnesium and sulfate. According to the local prescribing information, the pH of the solution ranges between 5.5 and 7.0. It is tremendously hyperosmolar (2000mOsm/kg) and would therefore do some serious damage to small veins it were infused directly into them; a 10mmol/100ml saline solution is usually mixed for peripheral administration. Interestingly, for a hyperosmolar fluid with serious sulfuric acid energy,  it does not cause any pain upon peripheral injection - in fact it has such excellent antinociceptive effects that it is equivalent to lignocaine for preventing the pain associated with propofol infusion.

Bioavailability and absorption

Apart from the IV formulation, magnesium ions can be administered in a whole number of different ways. The sulfate and chloride are available as intravenous formulations and can even be given nebulised. Sulfate, chloride, hydroxide and aspartate can also be given orally, though these formulations occasionally have unpleasant osmotic laxative effects. The underlying reason for these effects is also the reason for the variable and unpredictable bioavailability of oral magnesium. The uptake of magnesium from the small intestine is saturable. Most of it is absorbed passively by a paracellular route.  About 10% ends up getting into the systemic circulation by a transcellular mechanism, which seems to be some kind of facilitated transport regulated by plasma magnesium levels, which means that magnesium-deficient patients will absorb more by this mechanism, and magnesium replete patients will not. Overall, in healthy individuals with relatively normal magnesium levels (07-1.0 mmol/L), only about 30% of the oral magnesium dose will make its way into the circulation, and the rest will remain as an osmotically active ballast in the bowel.

pKa, solubility and protein binding

The pKa of magnesium sulfate heptahydrate is listed as -3.0; it is safe to say that it is fully water soluble at physiological pH.  Under normal circumstances, it is about 40% protein-bound (to albumin), behaving a lot like calcium in that regard. 

Distribution of magnesium

Magnesium is distributed to every body fluid compartment, but unequally. Specifically,  its intracellular entry is very carefully controlled. For this reason, when exogenous magnesium is administered as an infusion, most of it ends up in the extracellular compartment.  At least in pregnant women (who are the commonest guinea pigs for magnesium physiology experiments) the volume of distribution of magnesium is 0.25 to 0.442 L per Kg of body weight - much less than total body water. Thus, 20mmol of infused magnesium will distribute into a volume between 17.5 and 30.94 L (in a 70kg person), and the concentration in this distribution fluid would increase by 1.15 to 0.66 mmol/L.  This was confirmed in specific dose-finding study that graphed the rise of serum magnesium concentration following a bolus loading dose (and then a 24 hour infusion). 16mmol of MgSO4 were infused over 15 minutes. The serum concentration doubled from a baseline of 0.8 mmol/L to around 1.6-1.7mmol/L.

Elimination of magnesium

Magnesium is normally filtered at the glomerulus, and undergoes passive paracellular reabsorption in the thick ascending limb and active transcellular distal convoluted tubule. Of the two processes, the latter is the most responsible for the final net total of  magnesium excretion. It is a process which is saturable and which is probably the most important regulatory mechanism for controlling the plasma magnesium content. Under normal circumstances, the urinary loss of magnesium is relatively low, and most filtered magnesium is conserved. The normal net loss is apparently about 5mmol per day.  Excess magnesium rapidly exceeds the capacity of this active transport mechanism and results in the urinary excretion of magnesium (dare we call it, magnesiouresis?...). In this case, the excess magnesium has a half life of about 4 hours, or probably closer to 2 hours in pregnant women (expanded blood volume, hyperdynamic circulation, etc).

The various pharmacodynamic actions of magnesium sulfate

Magnesium sticks its nose into everything. Most authors, confronted with the need to explain its mechanism of action, typically hide behind the sheer scale of the answer. "Magnesium plays a vital role in over 300 reactions involving metabolism", they write, as if one could possibly count every minor molecular transaction which takes place with magnesium as a co-factor. How to even structure this? A couple of ideas come to mind. With a truly multi-system agent such as this, the natural instinct is to put everything into systems. An excellent example of this is the StatPearls article by Sharma (2020), from whence most of this material has been derived:

  • Respiratory effects
    • Magnesium acts as a bronchodilator
    • In high doses, can cause respiratory failure due to muscle weakness/paralysis
  • Cardiovascular effects
    • Antiarrhythmic effect (by acting as a physiological calcium channel blocker)
    • Slows AV nodal conduction (by the same effect)
    • Relaxes smooth muscle, causing vasodilation (this also underlies its tocolytic effect) - by increased calcium reuptake by the sarcoplasmic reticulum (i.e. less bioavailability of intracellular calcium)
  • Neurological effects
    • Anticonvulsant effects by post-synaptic inhibition of NMDA receptor (non-competitive antagonist)
    • Inhibits the release of acetylcholine at the neuromuscular junction
    • Relaxes smooth muscle, (this also underlies its tocolytic effect)
  • Electrolyte effects
    • Acts as a co-factor of the Na+/K+ ATPase pump
    • Co-factor of PTH synthesis; hypomagnesemia will cause hypoparathyroidism

Toxic effects, therefore, include:

  • Respiratory failure due to respiratory muscle paralysis
  • Vasodilation and hypotension
  • Bradycardia

Does anybody care about the sulfate?

Short answer: no.

Sulfate infusion has not attracted vigorous interest from authors. Once again, we refer to the brave heroes of the atomic age, who infused absurd amounts of sulfate into dogs, and concluded that "sulfate infusion appeared completely nontoxic" provided all other electrolytes were well corrected. They warn us that sulfate complexes with calcium, and some hypocalcemia will develop as a consequence of sulfate infusion.

References

Lu JF. Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia: pharmacokinetic principles. Clinical Pharmacokinetics. 38(4):305-14, 2000 Apr.

José R Weisinger, Ezequiel Bellorín-Font Magnesium and phosphorus Review Article The Lancet, Volume 352, Issue 9125, 1 August 1998, Pages 391-396

Keith W. Muir, MD, MRCP; ;Kennedy R. Lees, MD, FRCP Dose Optimization of Intravenous Magnesium Sulfate After Acute Stroke Stroke. 1998; 29: 918-923

Mackenzie Walser, Ann A. Browder ION ASSOCIATION. III. THE EFFECT OF SULFATE INFUSION ON CALCIUM EXCRETION Published in Volume 38, Issue 8 J Clin Invest. 1959; 38(8):1404–1411 doi:10.1172/JCI103916

Mohammed, S., and S. Goodacre. "Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis." Emergency Medicine Journal 24.12 (2007): 823-830.

Vu, M. K., et al. "The osmotic laxative magnesium sulphate activates the ileal brake.Alimentary Pharmacology and Therapeutics 14.5 (2000): 587-596.

Agarwal, Anil, et al. "Vein pretreatment with magnesium sulfate to prevent pain on injection of propofol is not justified." Canadian Journal of Anesthesia 51.2 (2004): 130-133.

Roth, Paul, and Eckhard Werner. "Intestinal absorption of magnesium in man." The International journal of applied radiation and isotopes 30.9 (1979): 523-526.

Blancquaert, Laura, Chris Vervaet, and Wim Derave. "Predicting and testing bioavailability of magnesium supplements." Nutrients 11.7 (2019): 1663.

Gröber, Uwe, et al. "Myth or reality—transdermal magnesium?." Nutrients 9.8 (2017): 813.

Connoley & Worthley: "Intravenous Magnesium" Critical Care and Resuscitation 1999; 1: 162-172

Fazekas, Tamás, et al. "Magnesium and the heart: antiarrhythmic therapy with magnesium." Clinical cardiology 16.11 (1993): 768-774.